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CN100528850C - Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation - Google Patents

Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation Download PDF

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CN100528850C
CN100528850C CNB028186761A CN02818676A CN100528850C CN 100528850 C CN100528850 C CN 100528850C CN B028186761 A CNB028186761 A CN B028186761A CN 02818676 A CN02818676 A CN 02818676A CN 100528850 C CN100528850 C CN 100528850C
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Prior art keywords
methyl
dihydro
ethoxy
phenyl
substituted
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CN1558905A (en
Inventor
D·B·洛维
P·L·维肯斯
马欣
张明宝
W·H·布洛克
P·D·G·科伊斯
I·A·穆格
A·斯托勒
汪明
Y·王
张承智
张海军
朱雷
M·特苏特苏米
J·N·里文格斯顿
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Bayer Healthcare LLC
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Bayer Pharmaceuticals Corp
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Abstract

本发明涉及式(I)新型茚满乙酸衍生物，其可用于治疗糖尿病、肥胖、高脂质血症、动脉粥样硬化等疾病。本发明还涉及茚满乙酸衍生物的式(II)和(III)中间体和制备方法。

Figure 02818676

The invention relates to a novel indane acetic acid derivative of formula (I), which can be used for treating diseases such as diabetes, obesity, hyperlipidemia, and atherosclerosis. The present invention also relates to intermediates of formulas (II) and (III) and preparation methods of indane acetic acid derivatives.

Figure 02818676

Description

Indane acetic acid derivatives and as the purposes and the preparation method of medicine, intermediate
The application requires the rights and interests of the U.S. Provisional Application sequence number 60/373,048 of the U.S. Provisional Application sequence number 60/308,500 of July 27 calendar year 2001 application and application on April 16th, 2002, and two provisional application contents integral body by reference are attached to herein.
Invention field
The present invention relates to indane acetic acid derivatives and the purposes in the medicinal compositions of diseases such as treatment diabetes, obesity, hyperlipidemia, atherosclerosis thereof.The invention still further relates to the intermediate and the preparation method that can be used for preparing indane acetic acid derivatives.
Background of invention
Type ii diabetes is more common diabetes, this diabetic subject's of 90-95% blood sugar increasing.Type ii diabetes exists the pancreatic beta cell amount to reduce, there are some peculiar defectives in insulin secretion and organize the susceptibility to Regular Insulin to reduce.The symptom of this diabetes and consequence comprise fatigue, frequent micturition, thirsty, blurred vision, often infect and ulcer healing slowly, diabetic nerve injury, retinopathy, little blood vessel and great vessels damage and heart and renal lesions.
Metabolic opposing to Regular Insulin is one of type ii diabetes key character.The glucose uptake that is characterized as insulin sensitivity organ (for example adipocyte and skeletal muscle) of insulin resistant produces the glucose obstacle with utilizing obstacle and suppressing liver.The insulin resistant of the plain shortage of functional islets, peripheral tissues and Regular Insulin can not suppress liver generation glucose and cause fasting plasma glucose to raise.The mechanism of pancreatic beta cell compensation insulin resistant is to improve the insulin secretion level.Yet the β cell can not keep so high secretion of Regular Insulin, and last glucose induction insulin secretion reduces, and causes the disorder of glucose stable state, causes occurring obvious diabetes then.Also have insulin resistant, hypertriglyceridemia, low hdl (HDL) property cholesterol and low-density lipoprotein (LDL) plasma concentration relevant with hyperinsulinemia raise.Insulin resistant and hyperinsulinemia are called " X syndrome " during with this class metabolic disease, and relevant closely with easy trouble hypertension and coronary heart disease.
Obesity is too much to accumulate fatty tissue.Too much serious medical conditions, for example type ii diabetes, hypertension, coronary heart disease, hyperlipidaemia, obesity and some malignant tumour take place in adipocyte easily.Adipocyte also can be by producing tumor necrosis factor alpha (TNF α) and other molecules influence glucose stable state.
Known many factors cause Atheromatosis, for example hypertension, diabetes, low HDL and high LDL.Diseases related cardiovascular disorder, coronary heart disease (CHD), cerebrovascular disease and the peripheral vascular disease of comprising of atherosclerosis.Coronary heart disease comprises that CHD death, myocardial infarction and coronary vasodilator form again.Cerebrovascular disease comprises ischemic stroke or hemorrhagic stroke and transient ischemic attack.
Therefore, although the medicine that exists some to can be used for treating above-mentioned disease still needs not only safety but also effectively disease therapeuticing medicine and effectively preparation method.
The present invention relates to can be used for treating the compound of following disease: for example X syndrome, glucose tolerance reduce for diabetes and relative disease, fasting plasma glucose raises and hyperinsulinemia; Fat; Atheromatosis, unusual lipidemia and relative disease be hypertriglyceridemia, low HDL cholesterol and hypercholesterolemia for example; Cardiovascular disorder; Cerebrovascular disease.
Detailed Description Of The Invention
The present invention includes following formula I compound and pharmacy acceptable salt thereof and ester:
Figure C0281867600321
Wherein
R is H or C 1-C 6Alkyl;
R 1Be H, COOR, C 3-C 8Cycloalkyl or
C 1-C 6Alkyl, C 2-C 6Alkenyl or C 1-C 6Alkoxyl group, each group can not be substituted or replaced by fluorine, methylenedioxyphenyl or phenyl, and wherein phenyl can not be substituted or by R 6Replace;
R 2For H, halogen or be not substituted or by C 1-C 6The C that alkoxyl group, oxo, fluorine replace 1-C 6Alkyl; Perhaps
R 2Be phenyl, furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, pyrrolidyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperazinyl or morpholinyl, each group can not be substituted or by R 6Replace;
R 3Be H, C 1-C 6Alkyl or be not substituted or by R 6The phenyl that replaces;
X is O or S;
R 4Be C 1-C 6Alkyl or C 3-C 8Cycloalkyl, arbitrary group can not be substituted or by fluorine, oxo or be not substituted or by C 1-C 6The C that alkoxyl group or phenyl replace 1-C 6Alkoxyl group replaces, and wherein phenyl is optional by R 6Replace; Perhaps
Arbitrary group can be replaced by following group: phenyl, naphthyl, furyl, thienyl, pyrryl, tetrahydrofuran base, pyrrolidyl, pyrrolinyl, tetrahydro-thienyl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, triazolyl oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydro benzo furyl, benzothienyl, the dihydrobenzo thienyl, indyl, indolinyl, indazolyl benzoxazolyl, benzothiazolyl, benzimidazolyl-, the benzoisoxazole base, the benzisothiazole base, Ben Bing Er Evil cyclopentadienyl, quinolyl, isoquinolyl, quinazolyl Kui oxazolinyl (quinoxazolinyl), the dihydrobenzopyrans base, thiochroman base or 1,4-benzodioxan base, each group can not be substituted or by R 6Replace; Perhaps C 1-C 6Alkyl also can be by C 3-C 8Cycloalkyl or phenoxy group replace, and wherein phenoxy group can not be substituted or by R 6Or following group replaces: phenyl, naphthyl, furyl, thienyl, pyrryl, tetrahydrofuran base, pyrrolidyl, pyrrolinyl, tetrahydro-thienyl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, triazolyl oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydro benzo furyl, benzothienyl, the dihydrobenzo thienyl, indyl, indolinyl, indazolyl benzoxazolyl, benzothiazolyl, benzimidazolyl-, the benzoisoxazole base, the benzisothiazole base, Ben Bing Er Evil cyclopentadienyl, quinolyl, isoquinolyl, quinazolyl Kui oxazolinyl, the dihydrobenzopyrans base, thiochroman base or 1,4-benzodioxan base, each group can not be substituted or by R 6Replace;
Perhaps
R 4Be phenyl, naphthyl, furyl, thienyl, pyrryl, tetrahydrofuran base, pyrrolidyl, pyrrolinyl, tetrahydro-thienyl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, triazolyl oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydro benzo furyl, benzothienyl, the dihydrobenzo thienyl, indyl, indolinyl, indazolyl benzoxazolyl, benzothiazolyl, benzimidazolyl-, the benzoisoxazole base, the benzisothiazole base, Ben Bing Er Evil cyclopentadienyl, quinolyl, isoquinolyl, quinazolyl Kui oxazolinyl, the dihydrobenzopyrans base, thiochroman base or 1,4-benzodioxan base
Each group can not be substituted or by R 6Or following group replaces: phenyl, furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, pyrrolidyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperazinyl, morpholinyl, Ben Bing Er Evil cyclopentadienyl, dihydro benzo furyl, indyl, pyrimidyl or phenoxy group, each group can not be substituted or by R 6Replace;
R 5Be H, halogen or the optional C that is replaced by oxo 1-C 6Alkyl;
R 6Be halogen, CF 3, the optional C that is replaced by oxo or hydroxyl 1-C 6Alkyl or the optional C that is replaced by fluorine 1-C 6Alkoxyl group.
More than the term of Shi Yonging has following implication in this article:
" C 1-C 6Alkyl " be meant 1 straight or branched alkyl to about 6 carbon atoms.Such group comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, neo-pentyl, 2-amyl group, n-hexyl, 3-hexyl, 2,3-dimethylbutyl etc.
" C 2-C 6Alkenyl " be meant and comprise 2 straight or branched thiazolinyls to about 6 carbon atoms and one or more pairs of keys.Such group comprises vinyl, propenyl, pseudoallyl, 2-isobutenyl, 4-pentenyl, 5-hexenyl etc.
" C 3-C 8Cycloalkyl " be meant 3 saturated mono cycloalkyl to about 8 carbon atoms, comprise such as groups such as cyclopropyl, cyclopentyl, cyclohexyl.
" C 1-C 6Alkoxyl group " be meant 1 straight or branched alkoxyl group to about 6 carbon atoms, comprise such as following group: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.
" halogen " is meant fluorine, chlorine, bromine or iodine.
When pointing out that alkyl, cycloalkyl, alkenyl or alkoxyl group are replaced by fluorine, can on any effective carbon atom, be replaced until perfluor by one or more fluorine atoms replacements.
When pointing out that alkyl substituent is replaced by oxo, be meant that alkyl is replaced by doubly linked oxygen, the coupled carbon of Sauerstoffatom constitute together carbon back-(C=O)-.
When pointing out that any part is substituted, can contain the substituting group of one or more regulations at any active position of described part, each substituting group can be independent of any other substituent definition, so each substituting group can be identical or different.
Term " optional replace () " is meant that one or more substituting groups that the part of being modified by this term can not be substituted or be prescribed replace.
R 3Can be connected 4 of formula I compound heterocyclic moiety or 5 (promptly on arbitrary effective carbon atom), therefore, the rest part of molecule will be connected on remaining effective carbon atom.
The present invention is described but not the formula I examples for compounds that the present invention limits is by any way listed in the table 1.
The illustrative examples of table 1 formula I compound
Figure C0281867600361
Figure C0281867600362
Figure C0281867600371
Figure C0281867600381
Figure C0281867600391
Figure C0281867600401
Figure C0281867600411
Figure C0281867600421
Figure C0281867600431
Numbering R 1 R 2 R 3 R 4 R 5 X
192 CH 3 Et CH 3 RhOCH 2 H O
193 CH 3 Et CH 3 PhOCH 2 H S
194 CH 3 Et CH 3 PhCH 2OCH 2 H O
195 CH 3 N-propyl CH 3 PhOCH 2 H O
196 CH 3 N-propyl CH 3 PhOCH 2 N-propyl O
197 CH 3 Normal-butyl CH 3 PhOCH 2 H O
198 CH 3 N-hexyl CH 3 PhOCH 2 H O
199 CH 3 N-hexyl CH 3 PhOCH 2 H S
200 CH 3 N-hexyl Sec.-propyl 3-Cl Ph H O
201 CH 3 N-hexyl Ph 3-Cl Ph H O
202 CH 3 CH 3OCH 2 CH 3 PhOCH 2 H O
203 CH 3 Ph Normal-butyl 3，4-di-FPh H O
204 CH 3 3-FPh CH 3 The 1-naphthyl H O
205 CH 3 The 4-pyridyl H 4-CF 3Ph H O
206 CH 3 The 4-pyridyl H 4-CF 3Ph H S
207 CH 3 Cl CH 3 3，5-di-F-Ph H O
208 CH 3 Br CH 3 CF 3CF 2 H O
209 CH 3 Br Normal-butyl CF 3CF 2 H O
210 CH 3 Br Normal-butyl CF 3CF 2 Br O
211 CH 3 Br Ph CF 3CF 2 Br O
212 CH 3 The 2-furyl CH 3 Isobutyl- H O
213 CH 3 The 2-furyl CH 3 Isobutyl- H S
214 CH 3 The 2-furyl CH 3 2-F-4-CF 3Ph H O
215 CH 3 The 2-furyl CH 3 The 2-naphthyl H O
216 CH 3 The 2-furyl i-Pr Isobutyl- H O
217 CH 3 EtCO N-propyl 3-CH 3O Ph EtCO O
218 Et H H Cyclopropyl H O
219 Et H H 4-FPh H O
220 Et H H 3，5-di-F-Ph H O
221 Et H H 4-Cl PhCH 2 H O
222 Et H H The 2-quinolyl H O
223 Et H CH 3 PhCH 2 H O
224 Et H CH 3 4-FPhCH 2 H O
225 Et H CH 3 3，4-di-F-PhOCH 2 H O
Figure C0281867600451
Figure C0281867600461
Figure C0281867600471
Figure C0281867600481
Figure C0281867600491
Figure C0281867600501
Figure C0281867600511
Figure C0281867600521
Figure C0281867600531
Figure C0281867600551
Figure C0281867600571
Figure C0281867600581
Figure C0281867600591
Figure C0281867600601
Figure C0281867600611
The salt of formula I compound can make the compound and appropriate organic or inorganic acid reaction preparation of the free property alkali form of purifying separately in the last separation and the purification phase in-situ preparing of compound after perhaps leading to, separate the salt that forms thus then.Equally, when formula I compound comprises carboxylic moiety (for example R=H), the salt of described formula I compound can be prepared as follows: make itself and suitable mineral alkali or organic bases reaction separately, separate the salt that forms thus then.Term " pharmacy acceptable salt " is meant the atoxic relatively mineral acid or the organic acid addition salt (referring to for example Berge etc., J.Pharm.Sci.66:1-19,1977) of The compounds of this invention.
The exemplary salt of formula I compound comprises conventional non-toxic salt and the quaternary ammonium salt that for example generates with mineral acid or organic acid according to method well-known in the art.For example such acid salt comprises acetate, adipate, alginate, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cinnamate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthic acid, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, itaconate, lactic acid salt, maleate, mandelate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, sulfonate, tartrate, thiocyanate-, tosylate, undecane hydrochlorate etc.
Alkali salt comprise an alkali metal salt (as sylvite and sodium salt) for example, alkaline earth salt (as calcium salt and magnesium salts) and with the ammonium salt of organic bases (as dicyclohexyl amine and N-methyl D-glycosamine).In addition, the basic nitrogen group that contains in the conjugate base can be with for example following reagent is quaternized: elementary alkyl halide, for example muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl, for example sulfuric ester of dimethyl, diethyl and dibutyl; And the sulfuric acid diamyl ester, long-chain halogenide is muriate, bromide and the iodide of decyl, dodecyl, tetradecyl and stearyl-for example; Aralkyl halide, for example benzyl and phenethyl bromide etc.
Formula I ester of the present invention is atoxic pharmaceutically acceptable ester, for example alkyl ester, for example methyl ester, ethyl ester, propyl diester, isopropyl esters, butyl ester, isobutyl or amyl group ester.Also can use other ester, for example methyl ester or phenyl C 1-C 5Alkyl ester.Formula I compound can comprise the alcohol groups reaction that makes suitable acid anhydrides, carboxylic acid or chloride of acid and formula I compound by various ordinary method esterifications.Promoting the alkali of acylation reaction (for example 1, two [dimethylamino] naphthalenes of 8-or N, N-dimethyl aminopyridine) to exist down, suitable acid anhydrides can react with alcohol.In the presence of dewatering agent (for example dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethyl carbodiimide) or other water-soluble dewatering agent and optional acylation catalyst; suitable carboxylic acid can react with alcohol, and described dewatering agent is used for except that anhydrating to drive reaction.In the presence of trifluoro-acetic anhydride and optional pyridine, perhaps at N, N-carbonyl dimidazoles and pyridine exist down, use suitable carboxylic acid also can realize esterification.Chloride of acid can be finished with acylation catalyst (for example 4-DMAP or pyridine) with the reaction of alcohol.
Those of skill in the art will readily appreciate that other method that how to complete successfully above-mentioned reaction and esterifying alcohol.
In addition, in any aforesaid method that forms ester, the susceptibility of formula I compound or reactive group may need protection or slough protection.Usually, blocking group can by ordinary method well-known in the art add and slough (referring to for example T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis; Wiley:New York, (1999)).
Formula I compound can comprise one or more asymmetric centers, and this depends on the position and the character of required different substituents.Unsymmetrical carbon can exist (R) or (S) configuration.Preferred isomers is to have to make formula I compound produce the isomer of bigger required bioactive absolute configuration.In some cases, because particular key rotation is limited, for example therefore the center key of two aromatic rings in the specific compound also exists asymmetric.
The substituting group of ring also may exist cis or transconfiguration, and the substituting group on two keys may exist Z type or E type.
The present invention has comprised all isomer (comprising enantiomer and diastereomer), no matter be the center of asymmetry type, still above-mentioned rotation constrained type is no matter be independent, pure or the purified isomer of part or its racemic mixture all are included in the scope of the present invention.The purifying of described isomer and the separation of described isomer mixture can be finished by standard technique known in the art.
The ad hoc approach that the preparation The compounds of this invention uses depends on required particular compound.All work in the selection in the preparation approach of particular compound of the present invention such as selected concrete X part and in the possible factors such as concrete substituting group of molecule different positions.Those of ordinary skills readily understand these factors.
Usually, The compounds of this invention can be by the similar approach preparation of standard technique known in the art and currently known methods.Usually, formula I compound can synthesize according to reaction process 1,2 and 3.How reaction process 1 and 2 demonstrations prepare intermediate, and the coupling in reaction process 3 of this intermediate provides formula I compound.
It " is C that reaction process 1 approach (A) provides the method for preparing compound 4 and 5, wherein R 1-C 6Low alkyl group or benzyl, R 3Be not hydrogen, X is O.The first step shows the acid groups of at first protecting commodity Aspartic Acid ester derivative compound 1 by method well-known in the art (for example with crossing the generation silyl ester), uses suitable R then 4-acid derivative R 4COY carries out the N-acylation reaction, and wherein Y is leavings group, for example halogen.At last, compound is sloughed protection by method well-known in the art, for example when being silyl ester, in the aqueous solution, progressively handling and obtain compound 2.Perhaps, the protection form of compound 1 and free carboxy acid (R for example in the presence of dewatering agent (for example DCC or EDCI) 4COOH) carry out condensation reaction and also can obtain compound 2.Compound 2 can be converted into compound 3, wherein R by several method then 3Definition in the cotype I compound.For example work as R 3During=Me, a kind of such method is well-known Dakin-West reaction, and this reaction uses acetic anhydride and pyridine to finish usually.Work as R 3When being not hydrogen, compound 2 can be converted into chloride of acid with the reagent such as thionyl chloride, then with Grignard reagent (R for example 3The Mg-halogen) reaction obtains compound 3. and also can use other method that generates the ketone of compound 3 from the derivative of acid and acid, and for example by using the Weinreb acid amides, it is well known to those skilled in the art.Then under sour dehydration conditions with the mixture of phosphoryl chloride for example or sulfuric acid and acetic anhydride, under heating, cyclisation compound 3 obtains compounds 4 usually, wherein X is O, R 3Be connected 5.
Those skilled in the art will be understood that compound 4 and compound 5 may exist and R 3, CH 2CO 2R " and CH 2CH 2Two kinds of positional isomers forms that the OH tie point is relevant.Use approach (B) can prepare such compound 4: R wherein 3Be connected the 4-position, and the carboxyl methyl chains is connected the 5-position, just two group positions and approach (A) obtain opposite.In approach (B), can under alkaline condition, (for example aqueous sodium hydroxide solution) use suitable R 4-acid derivative (R for example 4COY, wherein Y is leavings group such as chlorine) commodity amino-acid compound 6 acidylates can be obtained N-acylate 7.In the presence of strong non-nucleophilic base, compound 7 can prepare ketone ester 8 with the acetic ester coupling, wherein R then " is C 1-C 6Alkyl or benzyl.With dehydrated reagent POCl for example 3Cyclisation compound 8 obtains compounds 4, X=O wherein, R 3Be connected 4.In solvent (for example pyridine or acetonitrile/triethylamine), if desired under heating, compound 8 and nucleophilicity S reagent such as P 2S 5Reaction obtains compound 4, X=S wherein, R 3Be connected 4.
Reaction process 1 approach (C) has been described the method for preparing compound 4 with ketone ester 9 or 10, and wherein Y is a for example halogen of leavings group, and R " is C 1-C 6Alkyl or benzyl.Compound 9 or 10 any one all can be elected to be initial feed, this depends on the R in the final product 3Group is hydrogen or is connected 4 or 5.Therefore, compound 9 or 10 can obtain compound 4 with acid amides or sulphamide reaction, and wherein X is O or S.Ketone ester 9 or 10 is commercially available reagents, maybe can be by method preparation well-known in the art, and for example bromination commercially available reagent Y is the commodity ketone ester 9 and 10 of hydrogen.X is the acid amides (R of O 4C (=X) NH 2) can or can prepare with corresponding acid or chloride of acid by well-known method for the commodity carboxylic acid amides.X is the sulphamide (R of S 4C (=X) NH 2) can or can prepare with corresponding amide by currently known methods for the commodity sulphamide, for example use the LawessonShi reagent preparation.In the presence of alkali, ketone ester 9 and acid amides or sulphamide reaction obtain the compound 4 of Fen other Wei oxazole or thiazole, wherein R 3Be not hydrogen and be positioned at the 4-position.In the presence of alkali, ketone ester 10 and acid amides or sulphamide reaction obtain the compound 4 of Fen other Wei oxazole or thiazole, R 3Be positioned at the 5-position.
Approach (A), (B) and (C) obtain compound 4, wherein R separately 3And R 4Definition in the cotype I compound, R " is low alkyl group or benzyl.Then under condition well-known in the art, can for example lithium aluminium hydride, aluminum borohydride or other suitable hydride donor be reduced to compound 5 with compound 4 with reductive agent.
Reaction process 1
Figure C0281867600661
Reaction process 2 describe by in the presence of alkali with R 7-Y reaction is converted into shielded derivative 12, wherein R with commodity hydroxyketone 11 7For choosing wantonly by the C of phenyl or oxo replacement 1-C 6Alkyl, C 1-C 6Trialkylsilkl, arylalkyl silyl or COR 8R 8Be C 1-C 6Alkyl or optional by C 1-C 6The phenyl that alkyl, halogen or nitro replace; Y is a leavings group." C 1-C 6Trialkylsilkl " be meant that three independently are selected from and contain the 1 straight or branched alkyl to about 6 carbon atoms, each alkyl is connected on the silicon, comprises such group: trimethyl silyl, t-butyldimethylsilyl etc." arylalkyl silyl " is meant that the phenyl of at least one phenyl or replacement is connected to silicon, and there be independently being selected from of proper amt to contain 1 straight or branched alkyl to about 6 carbon atoms, each alkyl also is connected on the silicon, comprises such group: t-butyldiphenylsilyl, methyldiphenyl base silyl, dimethyl pentafluorophenyl group silyl etc." leavings group " comprises halogen for example I, Br and Cl; Carboxylicesters is acetic ester and triflutate for example; And the sulphonate of aryl and alkyl, for example methanesulfonates and p-toluenesulfonic esters etc.
Compound 12 is in the following way by R 2(defining among the cotype I) replaces, for example with the reaction of Electron Affinities halogen, perhaps at Lewis acid and R 2There is the ketone 13 that carries out Friedel-Crafts reaction formation replacement down in-Y (the same definition of Y).Perhaps, under metal catalytic, with complex compound well-known in the art and element compound for example palladium and nickel, the halogenated compound of Sheng Chenging (for example being replaced by bromine or iodine) can comprise tetrakis triphenylphosphine palladium (0) and [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) and similar nickel (0) and nickel (II) compound with the example that the reaction of many coupling objects generates the such catalyzer of the ketone that further replaces 13. in this way; The example of coupling object comprises boric acid and boron ester (well-known Suzuki coupling is carried out) in solvent such as toluene in the presence of alkali such as salt of wormwood; Organo-metallic is Grignard reagent, organic zinc (Negishi coupling) and organic tin derivates (Stille coupling) for example, and its reaction conditions is well known.In addition, with similar palladium or nickel catalyzator (Hartwig or Buchwald coupling), described halogenated compound can obtain the further ketone 13. of replacement with secondary amine (for example piperidines) coupling
Under conditions of similarity, compound 13 and halogen source or R 5-Y (R wherein 5Define among the cotype I) further reaction obtain dibasic compound 14.Wittig reaction and Horner-Emmons-Wadsworth conversion all are well known in the art, and arbitrary method can be used for being converted into compound 15 with 14.For example in the presence of highly basic (for example sodium hydride), " be low alkyl group, definition obtains compound 15 among the R cotype I for the reaction of compound 14 and trialkyl phosphine acyl acetic acid ester, wherein R.According to similar method, compound 13 can be converted into R 5Compound 15 for H.
15 the isomer mixture that does not produce in the tube reaction, no matter be isomer (E or Z) or both mixtures, can be by catalytic hydrogenation or with can 1, the hydride reagent reduction of 4-(conjugation) addition is converted into corresponding compounds 17, and this is well known to those skilled in the art.This approach is particularly conducive to preparation R 1Compound 17 for hydrogen.
R 1For the compound 17 of COOR can prepare by standard condensation reaction, for example Knoevenagel of called optical imaging reaction.In the case, in appropriate solvent, ketone 13 or 14 can react with suitable active hydrogen coupling reagent under acid reagent (for example titanium tetrachloride) or alkaline reagents (for example piperidines) effect.Product 15b (R 1Compound 15 for COOR) can be reduced to 17b (R 1Compound 17 for COOR), can be in the presence of alkali it be used another R 1The further alkylation of group, decarboxylize obtains 17d (R after the hydrolysis 1Be not COOH, and R is the compound 17 of H).Slough blocking group R behind the resterification 17d 7To obtain 17c.With the Fischer esterification process of called optical imaging, under standard conditions, carry out resterification: with acid and alcohol handle or with diazonium alkyl reagent or for example methyl-iodide or the methyl-sulfate reaction of Electron Affinities material.R 1For the compound 17 of alkoxyl group can be prepared as follows: under acid reagent (for example titanium tetrachloride) effect, ketone 13 or 14 and formula R 1CH=C (OR ") O-alkyl silyl (R 1Be alkoxyl group) the silylanizing enol ester carry out similar condensation reaction, then in the presence of hydrogen and above-mentioned catalyzer the reduction midbody compound 15, wherein R 1Be alkoxyl group.
Compound 13 or the 14 conventional coupled reactions via the Reformatsky reaction obtain R 1Compound 16 (formula II) or R for alkyl 1Compound 15a for H.With ketone and suitable organic zinc reagent condensation, described organic zinc is used zinc and R in position 1CHYCO 2The R preparation, wherein Y is a halogen.Formula R 1CHYCO 2The α of R-halogen ester cpds is commercial reagents or the R that buys by method halogenation well-known to those skilled in the art 1CH 2CO 2The R compound.
16 are converted into 17 can finish by the standard hydrogenation conditions, for example Pd/C and hydrogen; Can slough compound 17 (R wherein by standard method then 7Be blocking group) protection obtain compound 17c (R wherein 7Be hydrogen).For example work as R 7During for alkyl (as methyl), compound 17a can carry out the nucleophilicity cracking such as alkali metal mercaptide reagent and obtains by using.Perhaps, R 7For the compound 17 of methyl can be by reaction is converted into compound 17c as the bromo borine with Lewis acid.Work as R 7During for benzyl, compound 17 can be converted into 17c under hydrogenation conditions, finish with catalyzer such as palladium usually.R 7Slough blocking group R from compound 17 during not for hydrogen 7Other condition that produces oxy-compound 17c depends on the concrete blocking group that selected those skilled in the art know.
Reaction process 2
Figure C0281867600691
Note: a. (R " O) 2P (=O) CHR 1COOR, wherein R 1=H, highly basic
B.R 1CH 2COOR, wherein R 1=COOR, acidity or basic catalyst
c.R 1CHBrCO 2R，Zn
The final step of preparation I compound is shown in reaction process 3.With alcohol 5 (deriving from reaction process 1) and hydroxy indene 17c (deriving from reaction process 2) coupling, promote reaction acquisition formula I compound by the Mitsunobu coupled reaction with azodicarboxylate's reagent (for example DEAD) and phosphine (for example triphenylphosphine).Perhaps, with alcohol 5 hydroxyl and halogenating agent (for example thionyl chloride) or CCl 4The reaction of/triphenylphosphine; Perhaps in the presence of alkali, be converted into leavings group (for example halogen, tosylate (OTs) or methanesulfonates (OMs)) thereby acquisition compound 18 with Y-halogen compounds (wherein Y is tosyl group (Ts) or methylsulfonyl (Ms)) reaction.In the presence of alkali, compound 18 can react acquisition formula I compound with compound 17c.
In suitable solvent (for example methyl alcohol, THF, water or their mixture), heating down, be that the formula I compound of alkyl can be converted into the formula I compound that R is H with alkali (for example KOH) processing with R.Perhaps, this conversion can followingly be finished: react in suitable solvent (for example pyridine) with nucleophilic reagent (for example iodide or prussiate).In addition, when R is benzyl, can carries out hydrogenolysis by method well-known in the art and realize being cracked into the reaction that R is the formula I compound of H.
Reaction process 3
Figure C0281867600711
As X=S and R 4Group comprises the R of one or more stable reaction conditions to flow process 1 or 2 6During substituting group, reaction process 3a shows that another is used to obtain the approach of formula I compound.
Reaction process 3a
Figure C0281867600721
In flow process 3a, as implied abovely can be translated into 2-halogen thiazole 5a (Erlenmeyer etc., Helv.Chim.Acta 28:362-363,1945) then with thiocarbamide (being similar to reaction process 1 approach C) preparation thiazolamine 4.Finish the Mitsunobu coupled reaction by the method that is similar to reaction process 3 then, thereby product 19 is further processed introducing R by the catalytic crosslinked coupled reaction of palladium 4Substituting group.Obtain the formula I compound of R=H as the hydrolysis reaction of reaction process 3 descriptions.
The previous reaction flow process further specifies by specific embodiment described herein.
The conventional chemical method that salt of the present invention and ester can be easy to introduce previously by this paper prepares.
The invention further relates to new formula II compound (compound 16) shown in the reaction process 2 and formula III (compound 17 comprises compound 17a-d) compound.These compounds can be used for preparation I compound, further describe hereinafter.
The present invention includes formula II compound and formula III compound and salt thereof:
Figure C0281867600731
Wherein
R, R 1, R 2, R 3, R 4, R 5, R 6With X with the definition among the following formula I;
R 7Be H, optional by the C of phenyl or oxo replacement 1-C 6Alkyl, C 1-C 6Trialkylsilkl, arylalkyl silyl, COR 8, COOR 8Or
Figure C0281867600732
R 8Be C 1-C 6Alkyl or optional by C 1-C 6The phenyl that alkyl, halogen or nitro replace.
C 1-C 6Trialkylsilkl is meant that three independently are selected from and contain the 1 straight or branched alkyl to about 6 carbon atoms, and each alkyl is connected on the silicon, comprises such group: trimethyl silyl, t-butyldimethylsilyl etc.
The arylalkyl silyl is meant that the phenyl of at least one phenyl or replacement is connected to silicon, and there be independently being selected from of proper amt to contain 1 straight or branched alkyl to about 6 carbon atoms, each alkyl also is connected on the silicon, comprises such group: t-butyldiphenylsilyl, methyldiphenyl base silyl, dimethyl pentafluorophenyl group silyl etc.
The conventional chemical method that salt of the present invention can be easy to introduce previously by this paper prepares.
Formula II compound and formula III can each self-contained one or more asymmetric centers, depend on the position and the character of required different substituents.Unsymmetrical carbon can exist (R) configuration or (S) configuration.Preferred isomers is the isomer with absolute configuration, and formula II that described absolute configuration produces and formula III compound are used for production and have bigger required bioactive formula I compound.In some cases, because particular key rotation is limited, for example therefore the center key of two aromatic rings in the specific compound also exists asymmetric.
The substituting group of ring also may exist cis or transconfiguration, and the substituting group on two keys may exist Z type or E type.
The present invention has comprised all isomer (comprising enantiomer and diastereomer), no matter be the center of asymmetry type, still above-mentioned rotation constrained type, the isolating pure or purified isomer of part or its racemic mixture all are included in the scope of the present invention.The purifying of described isomer and the separation of described isomer mixture can be finished by the novel method of standard technique known in the art and this paper introduction.
For example, formula II compound may comprise a center of asymmetry (mark C-2) and the formula III compound can comprise two center of asymmetries (mark C-2 and C-1 ') that produce enantiomer and diastereomer.The above-claimed cpd of formula II and formula III compound and the example of other compound are listed in the table 2, and these examples only are used for illustration purpose.
Table 2
The illustrative examples of formula II and III compound
Figure C0281867600741
Figure C0281867600742
Figure C0281867600751
Figure C0281867600761
Figure C0281867600771
Another embodiment of the present invention is the improved method with certain specific isomer configuration compound that is used to prepare, and described specific isomer configuration is the configuration that formula I end product needs most.The above-mentioned midbody compound that obtains of improving one's methods is excessive higher than the possible diastereomer of midbody compound before this.
Former, for example there are not three-dimensional control, hydrogenation R in reaction process 2 step of hydrogenation 1For the formula II compound of alkyl may produce the uneven mixture of the diastereomer of formula III, wherein because the asymmetrical characteristic of initial feed, so a pair of enantiomer is received benefits.Separating such compound can finish by the following method: it is right progressively to separate enantiomer, splits each enantiomer by crystallization or chirality HPLC then.Initial feed is split as the mixture that single enantiomer produces a certain enantiomer enrichment earlier, can separate described enrichment enantiomer equally.
Yet, when needing the certain relevant configuration to be the compound of cis (hereinafter definition), R 1Productive rate is very low during for alkyl, because the step of hydrogenation conditions favouring of prior art is in other (promptly trans) diastereomer.
The required isomer configuration that obtains by originally improving one's methods is a cis, for example in formula Va compound and the Vb compound (in reaction process 4 and 5 describe), and R 92 ' mesomethylene carbon of group and pentamethylene ring is all below the plane or all more than the plane.Trans diastereomer is such compound: R for example 9More than the plane, and 2 ' methylene radical is below the plane.This is further specifying among Fig. 1 and 2 down, and wherein solid webge groove is meant the projection of the key more than the plane, and dotted line key is meant the projection of the key below the plane.
Fig. 1. the cis diastereomer of formula V
Figure C0281867600781
Fig. 2. the trans diastereomer of formula V
The present invention improves one's methods and obtains to have the excessive cis-compound of the diastereomer higher than common gained compound (the formula Va and the Vb that are described in Fig. 1 and flow process 4 and 5).
The initial feed midbody compound (reaction process 4 with 5 compound IV) that is used for this method is relevant with reaction process 2 Chinese style II compounds (compound 16), and can be by identical or similar method preparation.These intermediates can react under certain conditions and obtain and the relevant formula V compound of formula III compound (compound 17 and 17a in the reaction process 2), perhaps directly obtain formula I compound.Yet, because the restriction of improving one's methods has only some substituting group to be suitable for finishing this method.
So, the present invention relates to be used to prepare the method for the cis formula V compound of a large amount of enrichments,
Figure C0281867600791
Wherein
R 9For choosing wantonly by the methoxyl group of fluorine; C 2-C 6Alkoxyl group, C 1-C 6Alkyl or C 4-C 8Cycloalkyl, each group is optional by fluorine, methylenedioxyphenyl or optional by R 13The phenyl that replaces replaces;
R 10Be hydrogen; Fluorine; Optional by the methyl of fluorine or oxo replacement; Perhaps be not substituted or by C 1-C 6The C that alkoxyl group, oxo, fluorine or following group replace 2-C 6Alkyl: phenyl, furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, pyrrolidyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperazinyl or morpholinyl, each group can not be substituted or by R 13Replace; Perhaps
R 10Be phenyl, furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, pyrrolidyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperazinyl or morpholinyl, each group can not be substituted or by R 13Replace;
R 11Be halogen or the optional C that is replaced by oxo 1-C 6Alkyl;
R 12Be hydrogen; Optional by the methyl of fluorine or oxo replacement; The optional C that is replaced by phenyl, fluorine or oxo 2-C 6Alkyl; C 1-C 6Trialkylsilkl; The arylalkyl silyl; COR 14COOR 14Or
Figure C0281867600801
R 13Be fluorine, CF 3, the optional C that is replaced by oxo 1-C 6Alkyl or the optional C that is replaced by fluorine 1-C 6Alkoxyl group;
R 14Be C 1-C 6Alkyl or optional by C 1-C 6The phenyl that alkyl or fluorine replace;
R 15Be hydrogen, C 1-C 6Alkyl or by R 13The phenyl that replaces;
R 16For choosing wantonly by fluorine, the methyl that oxo or following group replace: phenyl, naphthyl, furyl, thienyl, pyrryl, tetrahydrofuran base, pyrrolidyl, pyrrolinyl, tetrahydro-thienyl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, triazolyl oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydro benzo furyl, benzothienyl, the dihydrobenzo thienyl, indyl, indolinyl, indazolyl benzoxazolyl, benzothiazolyl, benzimidazolyl-, the benzoisoxazole base, the benzisothiazole base, Ben Bing Er Evil cyclopentadienyl, quinolyl, isoquinolyl, quinazolyl Kui oxazolinyl, the dihydrobenzopyrans base, thiochroman base or 1,4-benzodioxan base, each group can not be substituted or by R 13Replace; Or
C 4-C 8Cycloalkyl or C 2-C 6Alkyl, arbitrary group can not be substituted or by fluorine, methoxyl group, optional by phenyl or C 1-C 6The C that alkoxyl group replaces 2-C 6Alkoxyl group, oxo replaces, or replaced: phenyl by following group, naphthyl, furyl, thienyl, pyrryl, tetrahydrofuran base, pyrrolidyl, pyrrolinyl, tetrahydro-thienyl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, triazolyl oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydro benzo furyl, benzothienyl, the dihydrobenzo thienyl, indyl, indolinyl, indazolyl benzoxazolyl, benzothiazolyl, benzimidazolyl-, the benzoisoxazole base, the benzisothiazole base, Ben Bing Er Evil cyclopentadienyl, quinolyl, isoquinolyl, quinazolyl Kui oxazolinyl, the dihydrobenzopyrans base, thiochroman base or 1,4-benzodioxan base, each group can not be substituted or by R 13Replace; Perhaps
C 2-C 6Alkyl, it also can be by C 4-C 8Cycloalkyl substituted or replaced by phenoxy group, wherein phenoxy group can not be substituted or by R 6Or following group replaces: phenyl, naphthyl, furyl, thienyl, pyrryl, tetrahydrofuran base, pyrrolidyl, pyrrolinyl, tetrahydro-thienyl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, triazolyl oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydro benzo furyl, benzothienyl, the dihydrobenzo thienyl, indyl, indolinyl, indazolyl benzoxazolyl, benzothiazolyl, benzimidazolyl-, the benzoisoxazole base, the benzisothiazole base, Ben Bing Er Evil cyclopentadienyl, quinolyl, isoquinolyl, quinazolyl Kui oxazolinyl, the dihydrobenzopyrans base, thiochroman base or 1,4-benzodioxan base, each group can not be substituted or by R 13Replace; Perhaps
R 16Be phenyl, naphthyl, furyl, thienyl, pyrryl, tetrahydrofuran base, pyrrolidyl, pyrrolinyl, tetrahydro-thienyl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, triazolyl oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydro benzo furyl, benzothienyl, the dihydrobenzo thienyl, indyl, indolinyl, indazolyl benzoxazolyl, benzothiazolyl, benzimidazolyl-, the benzoisoxazole base, the benzisothiazole base, Ben Bing Er Evil cyclopentadienyl, quinolyl, isoquinolyl, quinazolyl Kui oxazolinyl, the dihydrobenzopyrans base, thiochroman base or 1,4-benzodioxan base
Each group can not be substituted or by R 13Or following group replaces: phenyl, furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazole base, thiadiazolyl group, tetrazyl, pyridyl, pyrrolidyl, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperazinyl, morpholinyl, pyrimidyl or phenoxy group, each group can not be substituted or by R 13Replace;
X is O or S;
Described method is included in hydrogen source, catalyzer exists down, the optional existence under the alkali, and the racemic mixture of hydrogenation of formula IV compound or its isolating optically active isomer,
Figure C0281867600821
Wherein each substituent definition is the same.
The cis of a large amount of enrichments is meant that one or both are at least more than about 70% or 70% in the compound of Va or Vb configuration.This de (diastereomeric excess) that is equivalent to the cis diastereomer is at least about 40%.
The diastereomeric excess of cis diastereomer calculates with following formula:
Wherein
The diastereomeric excess of %de (cis) expression cis diastereomer
The concentration of [cis] expression cis diastereomer
The concentration of the trans diastereomer of [trans] expression,
And wherein
% cis+% is trans=and 100%.
Therefore, the 40%de of cis diastereomer is that mixture by 70% cis diastereomer and 30% trans diastereomer calculates:
The trans diastereomer of 40%de (cis)=70% cis diastereomer-30%
Catalyzer is meant any transition-metal catalyst (P.A.Chaloner that is used to realize hydrogenation well-known in the art, Handbook of Co-ordination Catalysis inOrganic Chemistry, Butterworth, 1986), and comprise homogeneous hydrogenation catalyst.Homogeneous catalyst is such catalyzer: be partially soluble in reaction medium at least and realize the reduction of two keys in the presence of hydrogen.Such catalyzer comprises for example ClRh[P (Ph) 3] 3(WilkinsonShi catalyzer), (1, the 5-cyclooctadiene) tricyclohexyl phosphine pyridine iridium (I) hexafluorophosphate, (1, the 5-cyclooctadiene) two (methyldiphenyl base phosphine) iridium (I) hexafluorophosphates (CrabtreeShi catalyzer) etc.
Alkali is meant a kind of its PK bBe enough to make it to give birth to salifiable material (referring to for example Advanced Organic Chemistry, the 3rd edition, Jerry March, pp 220-222) with carboxylic acid in position.The alkali that is used for this reaction can be any inorganic or organic bases, and can be dissolved in the reaction medium.Such alkali comprises for example single, double and three (C 1-C 6Alkyl) amine, for example Isopropylamine, Diisopropylamine, triethylamine etc.; Other primary amine, for example hexanaphthene methylamine and thanomin; Other secondary amine, for example morpholine and piperidines; And other tertiary amine, for example 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene and 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene; And mineral alkali for example oxyhydroxide, carbonate, the supercarbonate of basic metal and alkaline-earth metal, and optical active alkali quinine, cinchonine or (+)-or (-)-Alpha-Methyl benzylamine for example.
The chiral base that is used to split that such alkali is pointed out below for example also comprising.
Hydrogen source is meant any way that hydrogen is transported to reaction medium, comprises use hydrogen.Hydrogenation can be carried out in very wide hydrogen pressure scope, just from about normal atmosphere to about 1000psi, preferably from about 20 to about 100psi.Suitable hydrogenation solvent includes but not limited to protonic solvent for example ethanol, methyl alcohol, water, 2-propyl alcohol (proponal), the trimethyl carbinol, methylcellulose gum etc. and their mixture, the mixture of perhaps optional and mixable inert solvent (for example THF), hydrogenation catalyst, alkali and initial feed are partially soluble in such solvent separately at least.
The fractionation of initial formula IV indeneacetic acid derivative or formula V indane acetic acid derivatives can be finished by method well-known in the art, for example use opticity alkali as resolving agent, for example be easy to the alkali that obtains such as quinine, cinchonine or (+)-or (-)-Alpha-Methyl benzylamine.The selection of alkali will be depended on the salifiable dissolution characteristics of shape, therefore can be easy to finish fractionation by different recrystallization.By the alkali that selection has opposite absolute configuration, can finish the separation of the salt of each enantiomer.For example, for the embodiment of explanation in the reaction process 4, can isolate required enantiomer IVc or IVd, and turn to formula IV initial feed by racemization under alkaline condition and can reclaim unwanted isomer.
Suitable recrystallisation solvent is meant that a kind of diastereomeric salt of mixture is bigger than alternative solvability in such solvent, makes them to separate by recrystallization.Such solvent comprises for example acetonitrile, acetone, the trimethyl carbinol, 2-propyl alcohol, ethanol, methyl alcohol etc. and their mixture.
Inorganic acid aqueous solution comprises mineral acid for example commonly used, for example hydrochloric acid or sulfuric acid etc.
Described method can be begun (referring to reaction process 4) by the racemic modification of formula IV or begins (referring to reaction process 5) by the formula V compound that has at an asymmetric carbon corresponding to the configuration of required final product.Although two kinds of treatment processs will obtain the final product (V) of the cis-configuration of required a large amount of enrichments, preferably bring into use pure configuration usually.
An embodiment of present method is showed in the example of reaction process 4, may further comprise the steps:
(1) with suitable alkaline resolving agent processing production IVc and the diastereomeric salt of IVd,
(2) thus crystallization separates diastereomeric salt IVc and IVd in suitable recrystallisation solvent,
(3) the optional processing with inorganic acid aqueous solution discharges each enantiomorph IVa and IVb from isolating salt,
(4) by in the presence of homogeneous hydrogenation catalyst, suitable solvent and alkali, with isolating diastereomeric salt IVc and IVd or independent enantiomorph IVa and IVb reduction, wherein M+ is selected from following positively charged ion: basic metal, alkaline-earth metal, ammonium and single, two, three or tetra-allkylammonium or aralkyl ammonium, R 9-R 12Definition the same.
The enantiomeric purity of product Va and Vb will correspond respectively to used isomer IVa or the enantiomeric purity of IVb, but will not comprise a large amount of any other (trans) diastereomers.
Reaction process 4
Figure C0281867600851
Second embodiment of present method showed in reaction process 5, may further comprise the steps:
(1) by the hydrogenation in the presence of homogeneous hydrogenation catalyst, suitable solvent and alkali formula IV indene carboxylic acid is reduced,
(2) handle the diastereomeric salt that V generates Vc and Vd with suitable alkaline resolving agent,
(3) thus crystallization separates diastereomeric salt Vc and Vd in suitable recrystallisation solvent,
(4) by the inorganic acid aqueous solution processing each enantiomorph Va and Vb are discharged from isolating salt.
Reaction process 5
By method well-known in the art, for example the crystallization of chirality HPLC, chirality salt derivative, chiral ester derivative etc. can perfect IV or the fractionation of the racemic modification of formula V compound.
The absolute chirality of IVa, IVb, IVc, IVd, Va and Vb can be determined by several method well-known in the art.X-ray crystallization process can suitably be determined to provide such information under the condition at some.For example exist the crystallization unit cell of another component (for example the chiral separation agent or the auxiliary agent of salt, complex compound or covalently bound group form) of known chirality can carry out such detection.In the compound that will analyze, comprise the atomic time (for example bromine or iodine) of enough quality, can utilize other method heavy atom scattering technology known in the art.Also can use other method that relates to optical characteristics and use plane polarized light.For example those skilled in the art can understand such as garden two chromatographic techniques and can be applied to specified structure or structure type.
Can list below with the specific examples of the intermediate of the inventive method preparation, but they only are used for demonstration but not restriction, these intermediates can be used to prepare the formula I compound with identical absolute configuration.
Figure C0281867600881
R 1The formula III compound of=H also can be prepared as the opticity form with the method for flow process 6 general introductions.Can split racemate (formula III, the wherein R of 17a by the following method 1Be H): obtain 17f with Amano Lipase PS selectivity enzymatic hydrolysis.Perhaps can prepare 17e, then it be split by the following method by hydrolysis 17a: the diastereomeric salt that crystallization and optically active amines (for example (S)-(-)-Alpha-Methyl-benzylamine) generate, then with the described salt regeneration of mineral acid treatment carboxylic acid.Can further 17f be converted into intermediate 17g and 17h by the similar method that is used for preparation feedback flow process 2 17c: slough R behind the resterification 7Blocking group.
Reaction process 6
Figure C0281867600891
Formula I compound is effective to treat type ii diabetes (comprising relevant diabetic hyperlipemia and other diabetic complication) and is used for a large amount of other relevant therewith pharmaceutical uses, for example hyperglycemia, hyperinsulinemia, glucose tolerance reduction, fasting plasma glucose rising, unusual lipidemia, hypertriglyceridemia, X syndrome and insulin resistant.In addition, The compounds of this invention also is effective to regulate such as the appetite and the ingestion of food of obesity and is used for the treatment of Atheromatosis, hyperlipidaemia, hypercholesterolemia, low HDL, hypertension, cardiovascular disorder (comprising atherosclerosis, coronary heart disease, coronary artery disease and hypertension), cerebrovascular disease and peripheral vascular disease; And be used for the treatment of lupus, polycystic ovarian syndrome, oncogenesis and hyperplasia.Formula I compound also can be used for treating following dependency physiological maladies: for example cytodifferentiation produces the lipid accumulation cell; Regulate insulin sensitivity and blood glucose levels (relate to pancreatic beta cell dysfunction for example, insulin secretion tumour and/or because synalbumin autoantibody, AIRA or pancreatic beta cell produced the autoimmune hypoglycemia disease that the autoantibody of hormesis causes); Cause forming the scavenger cell differentiation of atherosclerotic plaque; Inflammatory reaction; Oncogenesis; Hyperplasia; Adipocyte genetic expression; The adipocyte differentiation; Pancreas beta cell amount reduces; Insulin secretion; Tissue is to the susceptibility of Regular Insulin; The growth of liposarcoma cell; Polycystic ovary disease; Chronic ovulation stops; The excessive androgen mass formed by blood stasis; Progesterone produces; Steroid generates; Redox potential and oxidative stress in the cell; Nitric oxide synthase (NOS) produces; Gamma glutamyl transpeptidase, catalase, plasma triglyceride, HDL and LDL cholesterol increase etc.
Useful especially formula I compound of the present invention is the compound that effectively reduces blood glucose concentration and S-TG concentration and rising serum hdl cholesterol concentration.
Therefore, expection formula I compound of the present invention is valuable medicine.Therefore, embodiment of the present invention comprises the method for a kind of treatment patient's (comprising Mammals) above-mentioned various diseases, and this method comprises and gives the formula I compound compositions that described patient comprises effective therapeutic goal disease amount.
As above narrate, formula I compound can give or unite one or more other hypoglycemic drugs separately and give.Conjoint therapy comprises the pharmaceutical formulations that comprises formula I compound and one or more other hypoglycemic drugs and with their independent pharmaceutical dosage form giving construction I compound and each other hypoglycemic drug.For example formula I compound and hypoglycemic agents can give the patient together with single oral compositions (for example tablet or capsule), and perhaps various medicines give with oral preparations independently.
When using independent preparation, formula I compound and one or more other hypoglycemic drugs can be in the essentially identical times (for example simultaneously) or in the staggered time that separates (for example sequential) administration.
For example, formula I compound can be united one or more following other hypoglycemic agentss: Regular Insulin; Biguanides, for example metformin or buformin; Sulfonylurea, for example acetohexamide, P-607, tolazamide, tolbutamide, Glyburide, Glipizide, gliclazide; Or any other Regular Insulin succagoga, for example repaglinide and nateglinide; Alpha-glucosidase inhibitor, for example Acarbose, voglibose or miglitol; Or β 3-adrenoceptor agonists such as CL-316,243.
Formula I compound also can adopt its free alkali form or composition and be used for research and diagnosis or with the reference standard etc. that performs an analysis, this is well known in the art.Therefore, the present invention includes composition, comprise formula I compound or its salt or the ester and the inert support of significant quantity in the said composition.Inert support by not with the compound effects of being carried and to the carrying compound carrier be provided, transport instrument, any material of increase-volume, tracer material etc.The compound significant quantity is meant the dosage that ongoing particular procedure is produced certain effect or certain influence.
In another aspect, the invention provides the method for treatment patient disease state, wherein said disease is relevant with Regular Insulin, glucose, free fatty acids (FFA), cholesterol or the tri-glyceride of the harmful concentration of physiology in the blood, and this method comprises the formula I compound that gives the patient treatment significant quantity.In further embodiment, the invention provides a kind of method that is used for the treatment of the patient disease state, wherein said disease is relevant with Regular Insulin, glucose, free fatty acids (FFA) or the tri-glyceride of the harmful concentration of physiology in the blood, this method comprises the formula I compound that gives the patient treatment significant quantity and gives other hypoglycemic agents of patient treatment significant quantity, for example Regular Insulin, biguanide compound etc.
It is known because sulfonylurea and other Regular Insulin succagoga can stimulate Regular Insulin to discharge, but can not be effective to insulin resistant, and formula I compound can be effective to insulin resistant, and the combined utilization of imagination said medicine can be used for the treatment of the relative disease that existing defect of insulin secretion has insulin resistant again.Therefore, the present invention also provides a kind of method of the patient's of treatment type ii diabetes, and this method comprises giving construction I compound and one or more other hypoglycemic drugs for example sulfonylurea, biguanides, receptor, agonist, alpha-glucosidase inhibitor and Regular Insulin.Equally, formula I compound also can suffer from the patient's of unusual lipidemia and insulin resistant lipid feature with HMG Co-A reductase inhibitor (Statins), bile acide binding resin or fiber acid derivative combined utilization with improvement.Formula I compound can also be united the medicine of regulating hypertensive medicine (for example angiotensin-converting enzyme (ACE) inhibitor, beta-Blocking agent, calcium channel blocker) and regulating the patient's who suffers from insulin resistant or diabetes B body weight and be used together.
Following specific embodiment is used to illustrate the present invention, and should not be interpreted as any restriction to the scope of the invention
Specific embodiment
HPLC-electrospray ionization mass spectrum (HPLC ES-MS) adopts following equipment to obtain: Hewlett-Packard 1100 HPLC, dispose four pumps, variable-wavelenght detector, YMC Pro C18 2.0mm * 23mm post and Finnigan LCQ ion trap mass spectrometer (electron spray ionisation).In the gradient of HPLC use from 90%A to 95%B (4min).Buffer A is 98% water, 2% acetonitrile and 0.02%TFA, and buffer B is 98% acetonitrile, 2% water and 0.018%TFA.Carry out spectral scan with the different ions time at 140-1200amu according to the source amount of ions.
Proton ( 1H) nucleus magnetic resonance (NMR) spectrum is used Me in order to following Equipment Inspection: General ElectricGN-Omega 300 (300MHz) spectrograph 4Si (δ 0.00) or remaining protonated solvent (CHCl 3δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard.Carbon ( 13C) NMR composes in order to Equipment Inspection down: General Electric GN-Omega 300 (75MHz) spectrograph, and with solvent (CDCl 3δ 77.0; d 3-MeOD; δ 49.0; d 6-DMSO δ 39.5) as standard.
Use is bought
Figure C0281867600921
AD HPLC post carries out chiral separation, and wash-out uses hexane (1%-15%) gradient that adds 0.1% trifluoroacetic acid and contain Virahol.
Abbreviation and acronym
When abridging below using, they have following implication:
Ac 2The O acetic anhydride
ADDP 1,1 '-(azo dicarbapentaborane) two piperidines
Anhy is anhydrous
The BOC tert-butoxycarbonyl
The n-BuOH propyl carbinol
The t-BuOH trimethyl carbinol
The t-BuOK potassium tert.-butoxide
The CDI carbonyl dimidazoles
CD 3OD methyl alcohol-d 4
Figure C0281867600931
The diatomite filtration agent,
Figure C0281867600932
Corp.
CH 2Cl 2Methylene dichloride
The Cl-MS chemical ionization mass spectrometry
Conc is dense
The DCC dicyclohexylcarbodiimide
The DCM methylene dichloride
The De diastereomeric excess
The DEAD diethyl azodiformate
Dec decomposes
The DIA Diisopropylamine
DIBAL-H diisobutyl aluminium hydroxide
DMAP 4-(N, N-dimethylamino) pyridine
The DME glycol dimethyl ether
DMF N, dinethylformamide
The DMSO methyl-sulphoxide
EDCl 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
The Ee enantiomeric excess
The ELSD light scattering detector
The ES-MS electron spray mass spectrometry
The EtOAc ethyl acetate
EtOH ethanol (100%)
The EtSH sulfur alcohol
Et 2The O ether
Et 3The N triethylamine
GC-MS vapor-phase chromatography-mass spectroscopy
The HPLC high performance liquid chromatography
The IPA Isopropylamine
The LAH lithium aluminum hydride
The LC-MS C/MS (liquid chromatography-mass spectrography)
The LDA lithium diisopropylamine
The m/z mass-to-charge ratio
The MeCN acetonitrile
NMM 4-methylmorpholine
Ph 3The P triphenylphosphine
Pd (dppf) Cl 2[1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II)
Pd (PPh 3) 4Tetrakis triphenylphosphine palladium (0)
Pd (OAc) 2Palladium
P (O) Cl 3Phosphoryl chloride
Rf retention factor (TLC)
The RT residence time (HPLC)
The rt room temperature
The TEA triethylamine
The THF tetrahydrofuran (THF)
The TFA trifluoroacetic acid
The TLC tlc
The TMAD N,N,N
The TMSCl trimethylsilyl chloride
Embodiment 1
Preparation 2-(6-methoxyl group-1H-indenes-3-yl) methyl-butyrate
Figure C0281867600951
5-L four neck round-bottomed flasks configuration thermometer, condenser, addition funnel and the mechanical stirrer of oven drying.Under the argon atmospher protection; with 5-methoxyl group-1-indone (80.0g; 494mmol), Zn powder (Lancaster; 56.2g; the anhydrous THF suspension of 2L 865mmol) stirs at 60 ℃ (internal temperatures); slowly add bromide methyl butyrate (134.1g, 400mL anhydrous THF solution 741mmol) by addition funnel simultaneously.After adding finishes, reaction mixture is stirred 1h at 60 ℃ (internal temperature).Reaction is analyzed with the TLC aliquots containig, progressively handles with the 1N HCl aqueous solution then.After reaction finishes, it is cooled off with ice-water bath, slowly add 3L 1N HCl solution then.The jar temperature is remained on below 20 ℃.Extract mixture with 1LEtOAc then.Organic layer washes the 6.0-7.0 up to pH with water, uses saturated NaCl solution washing then, uses dried over sodium sulfate.Also obtaining yellow oil product (127g,＞99%) after the vacuum-drying except that desolvating.
1H NMR(DMSO-d 6)δ7.28(d，1H)，7.05(d，1H)，6.82(dd，1H)，6.22(s，1H)，3.72(s，3H)，3.60(m，1H)，3.58(s，3H)，3.28(s，2H)，1.95(m，1H)，1.80(m，1H)，0.88(t，3H)。
Embodiment 2a
Preparation 2-(6-methoxyl group-1H-indenes-3-yl) butyric acid
Figure C0281867600952
(14.0g adds KOH (6.4g, 5mL aqueous solution 113.8mmol) to the ester of embodiment 1 preparation in 140mLMeOH solution 58.9mmol).Reaction mixture stirs 2h 60 ℃ (jar temperature).TLC confirms to have transformed 70%.(3.0g, 100mL aqueous solution 53.6mmol) slowly adds in the jar with KOH then.Behind 1h, reaction is finished.After being cooled to room temperature, removal of solvent under reduced pressure.Resistates is dissolved in the 500mL water, washs with EtOAc then.Cool off water layer with ice-water bath, be acidified to pH＜3.0 with dense HCl then.Product is extracted in the 300mL methylene dichloride, and (dried over sodium sulfate is used in 2 * 100mL) washings to water then.Behind the filtering sodium sulfate, dichloromethane solution is stirred 2h with the 3.0g charcoal.By
Figure C0281867600961
Pad removes by filter charcoal.After removing the also vacuum-drying of desolvating, obtain light brown solid title product (12.5g, 95%). 1H NMR(DMSO-d 6)δ12.20(b，1H)，7.30(d，1H)，7.06(d，1H)，6.82(dd，1H)，6.22(s，1H)，3.75(s，3H)，3.45(t，1H)，3.30(s，2H)，1.90(m，1H)，1.78(m，1H)，0.90(t，3H)。
Embodiment 2b
Preparation 2-(6-methoxyl group-1H-indenes-3-yl) propionic acid
Figure C0281867600962
Begin to prepare this reactant according to the same steps as of introducing among embodiment 1 and the 2a with 5-methoxyl group-1-indone and 2 bromopropionic acid methyl esters.
Yield: 68%. 1H NMR(CD 2Cl 2)δ7.34(d，J＝9，1H)，7.07(d，J＝2，1H)，6.85(dd，J＝9，J＝2，1H)，6.32(m，1H)，3.82(m，4H)，3.36(m，2H)，1.56(d，J＝7，3H)。
Embodiment 3
Preparation (2S)-2-(6-methoxyl group-1H-indenes-3-yl) butyric acid
Figure C0281867600963
At room temperature, the racemize indenes acid of embodiment 2a preparation (300g, add in 4.5L acetonitrile solution 1.29mol) quinine (324g, 1.0mol).Mixture is stirred 1h, form solution.Remove a small amount of insoluble particle by the micro-fibrous filter vacuum filtration.Mechanical stirring filtrate is spent the night under argon atmospher then.Behind 24h, the solid sample analysis that takes a morsel confirms 76.2%ee.Stop in a couple of days stirring.Filtering suspension liquid.(3 * 200mL) washing leaching cakes are then at 40 ℃ of vacuum-drying 3h with acetonitrile.Solid is added the 4.5L acetonitrile to be dissolved up to all solids 70 ℃ of stirrings.Allow solution slowly cool to room temperature.Gained suspension at room temperature stirs 24h.Filtering suspension liquid.(3 * 250mL) washing leaching cakes are then at 40 ℃ of vacuum-drying 24h with acetonitrile.Be collected as white solid quinine salt (254.6g, 35.4% yield, 96.8%ee).
(544.3g 0.98mol) is dissolved in the 4.0L methylene dichloride and obtains settled solution with quinine salt.With itself and 4.0L 2N HCl solution vigorous stirring in the 22-L round-bottomed flask of band bottom valve.Behind 30min, standing mixt.Tell bottom, upper water solution 1L dichloromethane extraction.(3 * 2.0L) washings are used dried over sodium sulfate up to pH 5.0-6.0 to the dichloromethane layer water that merges then.Acquisition Off-white solid product after removing the also vacuum-drying of desolvating (230.8g, 99%, 96.8%ee). 1Racemoid matter among H NMR and the embodiment 2a 1H NMR unanimity.
Handle mother liquor with similar fashion and obtain (R) isomer.Perhaps, in order to realize racemization and to reclaim the racemize initial feed, mother liquor is handled under the alkaline aqueous solution condition.
Embodiment 4
Preparation (2S)-2-[(1S)-5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] butyric acid
The product that embodiment 3 is obtained (105g, 453mmol), ClRh (PPh 3) 3(21.0g, 5%eq.) and triethylamine (68.8g, EtOH 679.5mmol) (945mL) and THF (105mL) solution in the 2-L pressure bottle in 60psi H 216h vibrates under the atmosphere.Removal of solvent under reduced pressure.The gained mixture stirs in 1.5L 1N HCl solution and 1.5L methylene dichloride.(2 * 250mL) extract water layer with methylene dichloride.The dichloromethane layer that merges stirs with 1L 1N NaOH solution then with 1L 1N HCl solution washing.(2 * 0.5L) extract organic layer with 1N NaOH solution.(2 * 250mL) washings are slowly adding dense HCl solution acidifying (pH 2.0-3.0) to the water layer that merges below 15 ℃ with methylene dichloride.(2 * 1.5L) extractions, (2 * 0.5L) washings are up to pH 5.0-6.0 for water with methylene dichloride for acidic mixture.In usefulness salt water washing and after with anhydrous sodium sulfate drying, solvent evaporated under reduced pressure.Obtain light yellow oily product (101.0g, 95% yield, 96.8%ee). 1H NMR(DMSO-d 6)δ12.20(s，1H)，7.04(d，1H)，6.78(d，1H)，6.66(dd，1H)，3.70(s，3H)，3.28(m，1H)，2.72(m，2H)，2.32(m，1H)，2.06(m，1H)，1.80(m，1H)，1.50(m，1H)，1.36(m，1H)，0.82(t，3H)。
Embodiment 5a
Prepare suitable-2-[5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] butyric acid
Figure C0281867600981
With the acid of racemize indenes (embodiment 2,980mg, 4.2mmol), ClRh (PPh 3) 3(139mg, 0.15mmol), (378mg, EtOH 4.5mmol) (20mL) and water (10mL) suspension are at the 500mL pressure bottle 30h that vibrates under the 60psi nitrogen atmosphere for sodium bicarbonate.Once more with ClRh (PPh 3) 3(300mg 0.33mmol) adds reaction mixture, and continuous hydrogenation is 3 days again.After this, EtOH is removed in decompression, and resistates dilutes with 200mL water.Remove by filter black solid, (2 * 200mL) wash filtrate with EtOAc.Then with the aqueous solution with dense HCl acidifying, with methylene dichloride (2 * 100mL) extractions.Dried over sodium sulfate is used in the dichloromethane layer salt water washing that merges.Solvent removed in vacuo obtains light yellow oily indane acid (600mg, 60%).(d, 1H) (d, NMR peak integration ratio 1H) is carried out the NMR analysis, determines that the products therefrom mixture is that cis-isomeride accounts for main non-enantiomer mixture (87: 13) with cis δ 7.03 with trans δ 7.11.
Can product be split as optically active isomer by following operation: cis the indane acetic acid [(2R under mechanical stirring at room temperature, 1R) with (2S, 1S), 14.69g, 62.7mmol] acetonitrile (290mL) solution in disposable adding (R)-(+)-Alpha-Methyl benzylamine (8.49mL, 65.9mmol).The stirring of gained mixture is spent the night.Observe and form seldom solid.Reaction mixture is concentrated into dried, resistates the heating under be dissolved in acetonitrile (200mL).Magnetic begins to cause precipitation under stirring.The mixture stirring is spent the night.Solid collected by filtration is with a small amount of cold acetonitrile washing three times.Then vacuum-drying solid 1.5h (8.1g, 86%ee).Little wet solid obtains 6.03g (2S)-2-[(1S)-5-methoxyl group-2,3-dihydro-1H-indenes-1-yl with acetonitrile (120mL) recrystallization] butyric acid, (R)-Alpha-Methyl benzylamine salt (94.4%ee).From each filtrate, collect for the second time product (0.89g, 97.6%ee).The total recovery that splits is 31% (based on racemic (2S, 1S) Suan maximum inclusion is 62%).Product is consistent with products therefrom among the embodiment 4.
The optical purity of present embodiment and embodiment 4 also can be analyzed by chirality HPLC; Post: Chiracel AD, 4.6 (I.D.) * 250mm; Moving phase, A: contain the hexane of 0.1%TFA (trifluoroacetic acid), B: the IPA (Virahol) that contains 0.1%TFA; Method, no gradient 95%A (5%B), 20min; Flow velocity, 1.5mL/min; Detector (UV), 284nm.The retention time of four possible diastereomers be 5.163min (2S, 1R), 6.255min (2R, 1S), 10.262min (2R, 1R) and 14.399min (2S, 1S).First sprocket bit (2S or 2R) is meant the absolute configuration of the carbon (2-position) in abutting connection with carboxyl; The absolute configuration of second sprocket bit (1S or 1R) expression indane ring carbon (its 1).
The stereochemistry at each peak is distributed by following definite: the non-equalization of chirality HPLC analysis of compounds 5 (suitable/anti-) racemize non-enantiomer mixture, the peak that it provides four baselines to split.Peak 3 and 4, peak 1 and 2 expression enantiomers are right, based on the UV integration.By x ray structure analysis, the absolute configuration of compound peaks 4 is defined as 2S, 1S.Corresponding then enantiomer peak 3 must be defined as 2R, the 1R configuration.Obtain secondary product as reduction chiral acid (embodiment 3) as described in the embodiment 4, by be defined as with its comparison peak 1 (2S, 1R)-diastereomer (retention time: 5.363min, about 0.97% area).Remaining then peak 2 must be confirmed as having 2R, the compound of 1S configuration.
Embodiment 5b
Prepare suitable-2-[5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] propionic acid
Figure C0281867601001
The same procedure of introducing according to embodiment 4 begins to prepare this compound with (racemic) embodiment 2b, 71% yield, and＞99%de: 1H NMR (DMSO-d 6) δ 12.18 (s, 1H), 7.03 (d, J=8,1H), 6.75 (d, J=2,1H), 6.67 (dd, J 1=8, J 2=2,1H), 3.68 (s, 3H), 3.37 (m, 1H), 2.72 (m, 3H), 2.03 (m, 1H), 1.75 (m, 1H), 0.89 (d, J=7,3H); 13C NMR (CD 2Cl 2) δ 12.626,28.228,31.950,43.300,46.445,55.607,110.054,112.510,124.552,136.702,146.411,159.464,182.330.
Embodiment 6
Preparation (2S)-2-[(1S)-5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] methyl-butyrate
Figure C0281867601002
The acid of embodiment 4 preparation (220.0g, 0.94mol), sodium bicarbonate (237.0g, 2.82mol), CH 3(200g, 2.0L DMF suspension 1.41mol) stirs 18h to I under argon atmospher, room temperature.NMR analyzes and confirms 95% reaction.Add potassiumiodide (100g), restir 24h at room temperature makes complete reaction.In reaction mixture impouring 4.0L water, with EtOAc (2 * 2L) extractions.Organic layer successively water (2 * 1L), 1L 1N NaOH solution, water (2 * 1L) and the water washing of 500mL salt, use dried over sodium sulfate.After removing the also vacuum-drying of desolvating, obtain light yellow oily product (233g, 99%). 1H NMR(DMSO-d 6)δ6.90(d，1H)，6.78(d，1H)，6.66(dd，1H)，3.70(s，3H)，3.60(s，3H)，3.20(m，1H)，2.80(m，2H)，2.40(m，1H)，2.08(m，1H)，1.80(m，1H)，1.58(m，1H)，1.40(m，1H)，0.80(t，3H)。
Embodiment 7
Preparation (2S)-2-[(1S)-5-hydroxyl-2,3-dihydro-1H-indenes-1-yl] methyl-butyrate
Figure C0281867601011
The compound that under argon atmospher, prepares to embodiment 6 (233g, and slow adding aluminum chloride in the cold soln (ice-water bath) of 2.5L methylene dichloride 0.94mol) (630g, 4.7mol).The jar temperature is remained on below 20 ℃, and the reactant color becomes purple.(345mL 4.7mol) slowly adds in the reaction mixture, and internal temperature remains on below 15 ℃ with EtSH with addition funnel.After stirring 2h below 20 ℃, NMR analyzes and shows that reaction is near finishing.With the 2.5L frozen water under the slow impouring violent stirring of mixture in the jar.Separate organic layer, water layer 1L dichloromethane extraction.(4 * 1L) washings are used dried over sodium sulfate up to pH 6.0-7.0 to the dichloromethane layer water that merges then.Also obtaining white solid product (216g, 98%) after the vacuum-drying except that desolvating. 1H NMR(DMSO-d 6)δ9.10(s，1H)，6.78(d，1H)，6.58(d，1H)，6.50(dd，1H)，3.60(s，3H)，3.20(q，1H)，2.70(m，2H)，2.40(m，1H)，2.08(m，1H)，1.80(m，1H)，1.50(m，2H)，0.80(t，3H)。
Embodiment 8
Preparation 3-[(4-methyl benzoyl) amino]-the 4-oxopentanoie acid methyl esters
Figure C0281867601012
(250g, (440g 4.35mol), then slowly adds Me to the triethylamine of adding regime flow in (＜5 ℃) methylene dichloride of refrigerative 1.36mol) (4L) suspension to L-aspartic acid 8-methyl ester hydrochloride 3SiCl (324g, 2.99mol).Mixture is warming up to 25 ℃, stirs 1h, cooling (＜10 ℃) once more, the dropping Butyltriphenylphosphonium chloride (205g, 1.36mol).Under agitation allow mixture slowly rise to room temperature 16h.Reaction mixture with 1N HCl (500mL), salt solution (500mL) washing, is used dried over sodium sulfate with methylene dichloride (500mL) dilution.After removing the also vacuum-drying of desolvating, obtain white solid amide product (310g, 91%).Then it is dissolved in pyridine (1.25L), adds DMAP (5g).Slowly add acetic anhydride (840mL), then at 90 ℃ of reacting by heating thing 2h.With refrigerative solution impouring 7L frozen water, with 6L EtOAc extraction.Organic layer with 2NHCl (3 * 1L) and 1NNaOH (1L) washing, use dried over mgso, concentrated acquisition white solid title compound (301g, 93%).
Embodiment 9
Preparation [5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] methyl acetate
Figure C0281867601021
(280g 1.06mol) is dissolved in acetic anhydride (650mL) to the intermediate that embodiment 8 is prepared, and slowly adds the vitriol oil (60mL) then.The jar temperature reaches 80 ℃.Then reactant is remained on 85 ℃ of 1h, cooling, vacuum is removed acetic anhydride.In the resistates impouring frozen water (2L), with EtOAc (4L altogether) extraction.Organic layer stirs 1h with 1N NaOH (500mL), separates, and uses dried over mgso then, concentrates to obtain clarification oily title ester (223g, 87%), slowly is cured as white solid.
Embodiment 10
Preparation 2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] ethanol
Figure C0281867601022
(300g 1.22mol) is dissolved in THF (2.7L) to embodiment 9 preparation De oxazole esters, adds solid LiBH with 5g at every turn 4(26.6g 1.22mol), keeps temperature to be lower than 45 ℃ simultaneously.1 hour afterreaction is complete adding.Solvent is reduced to half volume, then in the impouring frozen water (3L).Slowly add 1N HCl (1L) acidifying mixture.Form white precipitate, filter collecting precipitation, obtain Suo Xu oxazole ester (214g, 83%) with the Vanadium Pentoxide in FLAKES drying at baking oven.
Embodiment 11
Preparation (2S)-2-((1S)-5-{2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group }- 2,3-dihydro-1H-indenes-1-yl) methyl-butyrate
Under room temperature, argon atmospher, with the hydroxy indene carboxylicesters of embodiment 7 preparation (208g, 889mmol), embodiment 10 preparation De oxazole ethanol (212g, 977mmol), ADDP (335g, 1.33mol), Ph 3(348g, the anhydrous THF suspension of 6.0L 1.33mol) stirs P. 1The HNMR monitoring reaction.After 2 days, further do not make progress.After the solids removed by filtration, THF is removed in decompression.Remaining mixture is stirred 10min in 3L 50/50EtOAc/ hexanes mixtures, generate more solid, remove by filter.Concentrated filtrate carries out identical step with it with the 25/75EtOAc/ hexanes mixtures.Except that after desolvating, silica gel (3.0kg) the post purification (methylene dichloride (10.0L) and 20% acetonitrile/methylene dichloride (10.0L) are as solvent) of gained oily mixture.Collection comprises the product part, concentrates then.Crude mixture is dissolved in the 4.0L methylene dichloride, and (3 * 1L) washings are to remove unreacted oxy-compound with 1N NaOH.The dichloromethane layer dried over sodium sulfate.After removing the also vacuum-drying of desolvating, obtain light yellow oily product (358g, 93%). 1H NMR(DMSO-d 6)δ7.78(d，2H)，7.30(d，2H)，6.90(d，1H)，6.75(d，1H)，6.65(dd，1H)，4.15(t，2H)，3.60(s，3H)，3.25(q，1H)，2.90(t，2H)，2.75(m，2H)，2.40(m，1H)，2.35(s，3H)，2.32(s，3H)，2.05(m，1H)，1.80(m，1H)，1.50(m，2H)，0.80(t，3H)。
Embodiment 12
Preparation (2S)-2-((1S)-5-{2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group }- 2,3-dihydro-1H-indenes-1-yl) butyric acid
Figure C0281867601041
At room temperature, (90.4g adds ester (325g, 3.9L THF solution 0.75mol) that embodiment 11 prepares to LiOH in 1.3L water 3.76mol) and the 1.3L MeOH solution.The solution becomes muddiness.At 60 ℃ of (jar temperature) heating 4h, TLC (50%EtOAc/ hexane) analyzes and confirms to transform about 50% with mixture.(30.1g, water 1.25mol) (200mL) solution adds reaction mixture with LiOH.Behind 2h, TLC analyzes and confirms about 85% reaction.(30.1g, water 1.25mol) (200mL) solution adds reaction mixture with LiOH once more.Behind 2h, TLC analyzes and confirms only remaining few initial ester.After reaction mixture was cooled to room temperature, THF and MeOH were removed in decompression.Residue diluted with water is up to solid dissolving (using 60L water altogether).Dense HCl solution is slowly added this aqueous solution up to pH 2.0-3.0.Solid collected by filtration, dried overnight under the cover vacuum.This solid is stirred 30min with 15L EtOAc and 2L 1N HCl solution.Isolate the EtOAc layer, with (2 * 1L) washings of 1N HCl solution.(4 * 2L) washings are until pH=5.0-6.0 for the organic phase water.Under the argon atmospher protection, by air distillation EtOAc solution is reduced to 2.5L, under not stirring, be cooled to room temperature then.Be settled out white solid.After in ice-water bath, further cooling off 2h, leach solid, with the cold EtOAc washing of 500mL.35 ℃ of high vacuum dry to constant weight, collect the white crystal end product (266g, 81%, 98%ee). 1H MR(CDCl 3)δ7.82(d，2H)，7.20(d，2H)，7.05(d，1H)，6.75(d，1H)，6.70(dd，1H)，4.20(t，2H)，3.42(q，1H)，2.95(t，2H)，2.80(m，2H)，2.50(m，1H)，2.35(s，3H)，2.32(s，3H)，2.20(m，1H)，1.90(m，1H)，1.65(m，1H)，1.45(m，1H)，0.90(t，3H)。Chiral purity, 99%ee, [α] D=+16.11 (CHCl 3), mp 149.5-150.5 ℃.
Embodiment 13
Preparation 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1- Base } butyric acid
Figure C0281867601051
Step 1.Be dissolved in 5-methoxyl group-indone (10g) solution of toluene (150mL) and add AlCl 3(15g).Mixture is refluxed 4h up to precipitation occurring.Cooling gained mixture is in its impouring frozen water (150mL).Leach precipitation, wash with water, the required product of air-dry then acquisition (8.5g, 90%).
Step 2.Bromotoluene (17g), 5-hydroxyl-indone (15g), salt of wormwood (20g) and 200mL acetone are mixed in round-bottomed flask (500mL).With the mixture 1h that refluxes.Filtering salt of wormwood, evaporated filtrate.The gained resistates obtains 18g product (75%) with the EtOAc crystallization.
Step 3. with 5-benzyloxy-indone (1.14g, 4.79mmol) and diethyl malonate (0.844g, THF 5.29mmol) (20mL) solution is cooled to 0 ℃ under argon atmospher, drip TiCl 4(10mL, the dichloromethane solution of 1M).The final pyridine (2mL) that adds.At room temperature stir the gained mixture overnight.After the filtration, EtOAc (30mL) is added filtrate.Organic layer is used dried over sodium sulfate with salt solution (20mL * 3) washing, then evaporation.Resistates separates acquisition 800mg product (50%) by silica gel chromatography.
Step 4.Step 3 product (1.7g) is dissolved in MeOH (25mL), adds the MeOH soup compound of Pd-C (300mg), is placed under the 60psi nitrogen atmosphere 6h in the Parr vibrator.Filter the back and concentrate, obtain 1.2g product (92%).
Step 5.At 0 ℃ with P (Ph) 3(420mg) and ADDP (420mg) be dissolved in THF (5mL), stir 10min.The THF solution of oxazole (300mg) and phenol (430mg) is added flask.Stir gained mixture 24h, filter then.Evaporated filtrate, the gained resistates separates acquisition product (320mg, 45%) by silica gel chromatography.
Step 6.The intermediate (160mg) of step 5 preparation is dissolved in THF (5mL), and iodic ether (0.5mL) and t-BuOK (50mg) are added solution, and stirring is spent the night.After the filtration, use TLC to isolate product 100mg (65%).
Step 7.The intermediate (30mg) of step 6 preparation is dissolved in DMSO (1mL).LiCl (160mg) is added flask.With the mixture 5h that refluxes.Isolate product 13mg (52%) from the gained mixture by TLC.
Step 8.As acquisition product: the LC-MS that the intermediate of step 7 preparation is hydrolyzed in the KOH aqueous solution as described in the embodiment 2, RT 3.57min, M+1 406; 1HNMR (CD 2Cl 2): δ 0.93 (t, 3H), 1.40-1.70 (m, 2H), 1.80-2.20 (m, 2H), 2.30 (s, 3H), 2.40 (m, 1H), 2.60-2.80 (m, 2H), 2.90 (t, 2H), 3.20-3.40 (m, 1H), 4.10 (t, 2H), 6.60 (dd, 1H), 6.70 (d, 1H), 7.00 (d, 1H), 7.30 (m, 3H), 7.90 (m, 2H).
According to the step of embodiment 1-13, the chirality HPLC separation method that uses summary partly to introduce under some situation simultaneously, adopt suitable initial feed to prepare with similar approach and the following compound of sign:
Embodiment 14
2-(5-{2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group }-2,3-dihydro-1H-indenes -1-yl) butyric acid
Figure C0281867601071
LC-MS，RT 3.70min，M+1420； 1H NMR(CD 2Cl 2)：δ0.93(t，3H)，1.40-1.70(m，2H)，1.80-2.20(m，2H)，2.30(s，3H)，2.35(s，3H)，2.40(m，1H)，2.60-2.80(m，2H)，2.90(t，2H)，3.20-3.40(m，1H)，4.10(t，2H)，6.60(dd，1H)，6.70(d，1H)，7.00(d，1H)，7.20(m，3H)，7.80(m，2H)。
Embodiment 15
(2S)-and 2-{ (1S)-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H- Indenes-1 base } butyric acid
Figure C0281867601072
Enantiomer is separated by chirality HPLC.LC-MS，RT 3.57min，M+1406； 1H NMR(CD 2Cl 2)：δ0.93(t，3H)，1.48(ddq，1H)，1.68(ddq，1H)，1.93(dddd，1H)，2.18(dddd，1H)，2.34(s，3H)，2.50(ddd，1H)，2.77(ddd，1H)，2.87(ddd，1H)，2.96(t，2H)，3.42(ddd，1H)，4.19(t，2H)，6.68(dd，1H)6.77(d，1H)。7.08(d，1H)，7.42(m，2H)，7.44(m，1H)，7.97(dd，2H)。 13C NMR：δ10.4，12.4，22.4，26.6，29.5，31.8，46.5，51.8，67.2，110.9，113.0，124.7，126.2，128.1，129.1，130.2，133.2，137.1，145.6，146.3，158.7，159.7，180.4。
Embodiment 16
(2S)-and 2-{ (1R)-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1-H- Indenes-1-yl } butyric acid
Enantiomer is separated by chirality HPLC.LC-MS，RT 3.57min，M+1406； 1H NMR(CD 2Cl 2)：δ0.93(t，3H)，1.61(ddq，1H)，1.69(ddq，1H)，1.99(dddd，1H)，2.19(dddd，1H)，2.47(s，3H)，2.52(ddd，1H)，2.73(ddd，1H)，2.89(ddd，1H)，3.11(t，2H)，3.31(ddd，1H)，4.21(t，2H)，6.66(dd，1H)6.74(d，1H)。7.13(d，1H)，7.55(m，2H)，7.61(m，1H)，8.05(dd，2H)。 13C NMR：δ10.5，12.2，23.8，24.8，30.3，31.5，46.4，50.9，66.1，110.8，112.6，125.9，127.4，123.6，129.8，133.3，129.7，137.0，148.4，146.5，158.2，160.5，181.0。
Embodiment 17
(2R)-and 2-{ (1R)-5-[2-(5-methyl-2-[4-aminomethyl phenyl]-1,3-oxazole-4-yl) oxyethyl group]-2,3- Dihydro-1H-indenes-1-yl } butyric acid
Figure C0281867601082
Enantiomer is separated by chirality HPLC.LC-MS，RT 3.70min，M+1420； 1H NMR(CD 2Cl 2)：δ0.95(t，3H)，1.40(m，1H)，1.70(m，1H)，1.90(m，1H)，2.20(m，1H)，2.30(s，3H)，2.35(s，3H)，2.50(m，1H)，2.60-2.80(m，2H)，2.90(t，2H)，3.40(dd，1H)，4.20(t，2H)，6.60(dd，1H)，6.70(d，1H)，7.10(d，1H)，7.20(m，3H)，7.80(m，2H)。
Embodiment 18
2-(5-{2-[5-methyl-2-phenyl-1,3-oxazole-4-yl] oxyethyl group }-2,3-dihydro-1H-indenes-1-yl) third Acid
Figure C0281867601091
LC-MS，RT 3.41min，M+1392； 1H NMR(CD 2Cl 2)：δ1.10(d，3H)，1.90(m，2H)，2.20(m，1H)，2.40(s，3H)，2.70-3.00(m，2H)，2.95(t，2H)，3.45(m，1H)，4.20(t，2H)，6.70(dd，1H)，6.80(d，1H)，7.10(d，1H)，7.45(m，3H)，8.00(m，2H)。
Embodiment 19
2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } third Diacid
Figure C0281867601092
LC-MS，RT 3.00min，M+1422； 1H MR(CD 2Cl 2)：δ1.90(m，2H)，2.40(t，3H)，2.60-3.00(m，3H)，3.40(t，2H)，3.70(m，1H)，4.20(t，2H)，6.60(dd，1H)，6.80(d，1H)，7.10(d，1H)，7.50(m，3H)，7.95(m，2H)。
Embodiment 20
3-oxyethyl group-2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H- Indenes-1-yl }-3-oxo propionic acid
Figure C0281867601093
LC-MS，RT 3.39min，M+1450； 1H MR(CD 2Cl 2)：δ1.20(t，3H)，2.00(m，1H)，2.30(m，1H)，2.40(s，3H)，2.90(m，2H)，3.10(t，2H)，3.80(m，1H)，4.20(t&q，4H)，6.70(dd，1H)，6.80(d，1H)，7.10(d，1H)，7.50(m，3H)，8.00(m，2H)。
Embodiment 21
2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl }-5- Phenylpentanoic acid
Figure C0281867601101
LC-MS，RT 3.98min，M+1396； 1H NMR(CD 2Cl 2)：δ1.40-1.80(m，4H)，1.90-2.20(m，2H)，2.35(s，3H)，2.40-3.00(m，5H)，2.90(t，2H)，3.35(m，1H)，4.10(t，2H)，6.60(dd，1H)，6.70(d，1H)，6.907.20(m，6H)，7.30(m，3H)，7.95(m，2H)。
Embodiment 22
2-(5-{2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group }-2,3-dihydro-1H-indenes -1-yl) propionic acid
Figure C0281867601102
LC-MS，RT 3.52min，M+1406； 1H MR(CD 2Cl 2)：δ1.10(d，3H)，1.90(m，2H)，2.20(m，1H)，2.30(s，3H)，2.31(s，3H)，2.70-3.00(m，2H)，2.95(t，2H)，3.40(m，1H)，4.10(t，2H)，6.60(dd，1H)，6.70(d，1H)，7.00(d，1H)，7.20(d，2H)，7.80(d，2H)。
Embodiment 23
2-(5-{2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group }-2,3-dihydro-1H-indenes -1-yl) caproic acid
Figure C0281867601111
LC-MS，RT 3.92min，M+1448； 1H NMR(CD 2Cl 2)：δ0.93(t，3H)，1.10-1.30(m，4H)，1.40-1.70(m，2H)，1.80-2.20(m，2H)，2.30(s，3H)，2.31(s，3H)，2.40(m，1H)，2.60-2.80(m，2H)，2.90(t，2H)，3.20-3.40(m，1H)，4.10(t，2H)，6.60(dd，1H)，6.70(d，1H)，7.00(d，1H)，7.20(d，2H)，7.80(d，2H)。
Embodiment 24
4-methyl-2-(5-{2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group }-2, the 3-dihydro -1H-indenes-1-yl) valeric acid
Figure C0281867601112
LC-MS，RT4.00min，M+1448； 1H NMR(CD 2Cl 2)：δ0.93(m，6H)，1.20(m，1H)，1.40-1.70(m，2H)，1.80-2.20(m，2H)，2.30(s，3H)，2.31(s，3H)，2.40(m，1H)，2.60-2.80(m，2H)，2.90(t，2H)，3.20-3.40(m，1H)，4.10(t，2H)，6.60(dd，1H)，6.70(d，1H)，7.00(d，1H)，7.40(d，2H)，8.40(d，2H)。
Embodiment 25
4-methyl-2-(5-{2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-4-yl] oxyethyl group }-2, the 3-dihydro -1H-indenes-1-yl)-the 4-pentenoic acid
Figure C0281867601121
LC-MS，RT 3.74min，M+1446； 1H NMR(CD 2Cl 2)：δ1.60(s，3H)，1.70(m，2H)，1.80-2.20(m，2H)，2.30(s，3H)，2.31(s，3H)，2.40(m，1H)，2.60-2.80(m，2H)，2.90(t，2H)，3.20-3.40(m，1H)，4.10(t，2H)，5.60(m，2H)，6.60(dd，1H)，6.70(d，1H)，7.00(d，1H)，7.20(d，2H)，7.80(d，2H)。
Embodiment 26
Via 2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) ethyl methane sulfonate ester and 2-(6-chloro-5-hydroxyl- 2,3-dihydro-1H-indenes-1-yl) methyl-butyrate
Preparation 2-{6-chloro-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H- Indenes-1-yl } butyric acid
Figure C0281867601122
Step 1.2-phenyl-4-methyl-5-Qiang base Yi Ji oxazole (500mg, add in 12.5mL THF solution 2.5mmol) methane sulfonyl chloride (0.21mL, 2.75mmol) and triethylamine (0.42mL, 3mmol).Under room temperature, argon atmospher, stirring reaction solution 2h, vacuum concentration then.The gained resistates is dissolved in ethyl acetate, with 1% aqueous hydrochloric acid (three times) and salt water washing.Use dried over sodium sulfate then, filter, vacuum concentration obtains product (617mg, 88%): ES-MS m/z 282 ((M+H) then +); HPLC RT 2.67; 1H MR (d 6-DMSO) δ 2.33 (s, 3H), 2.89 (t, 2H), 3.13 (s, 3H), 4.41 (t, 2H), 7.47-7.51 (m, 3H), 7.88-7.91 (m, 2H).
Figure C0281867601131
Step 2.(0.035mL 0.43mmol) adds 5-hydroxyl-2, and (100mg is in 2.15mL acetic acid solution 0.43mmol) for 3-dihydro-1-(2-methyl-butyrate) with SULPHURYL CHLORIDE.Reaction soln at room temperature stirs 30min, vacuum concentration then.The gained resistates is dissolved in ethyl acetate, water, saturated sodium bicarbonate aqueous solution and salt water washing.Use dried over sodium sulfate, filter, vacuum concentration obtains the required crude yellow oil shape of 63mg intermediate then, and it is directly used need not to purify: GC-MS 269, ((M+H) again +); GC RT (min) 8.71; 1H NMR (d 6-DMSO) δ 0.81 (t, 3H), 1.40-1.63 (m, 2H), 1.77-1.88 (m, 1H), 2.00-2.15 (m, 1H), 2.40-2.80 (m, 3H), 3.15-3.22 (m, 1H), 3.50 (s, 3H), 6.76 (s, 1H), 7.13 (s, 1H), 9.84 (s, 1H).
Step 3.(30.5mg, 0.6mL DMF solution 0.12mmol) is cooled to 0 ℃ to the product that step 2 is obtained in ice bath.Adding 60% then is scattered in sodium hydride in the oil (5.2mg 0.13mmol), removes ice bath.At room temperature behind the stirred reaction mixture 1h, add step 1 methanesulfonates (34mg, 0.12mmol).Reaction mixture at 50 ℃ of heating 24h, is cooled to 0 ℃ then.Add 9.6mg NaH (60% is scattered in the oil) once more, reheat 2h, after this reaction mixture is cooled to room temperature, stir 48h.At this moment, add ethyl acetate, dried over sodium sulfate is used in organic solution water and salt solution (three times) washing, filters, then vacuum concentration.The gained resistates obtains to be the product of non-enantiomer mixture (3: 1) (19mg, 35%): ES-MS m/z 454 ((M+H) by flash chromatography on silica gel method purification (5: 1 hexanes: ethyl acetate is as eluent) +); HPLC RT (min) 4.21; 1H NMR (d 6-DMSO) δ 0.80 (t, 3H), 1.38-1.63 (m, 2H), 1.79-1.90 (m, 1H), 2.02-2.14 (m, 1H), 2.34 (s, 3H), 2.51-2.57 (m, 1H), 2.63-2.84 (m, 2H), 2.91 (t, 2H), 3.19-3.25 (m, 1H), 3.49 (s, 2.3H), 3.58 (s, 0.7H), 4.22 (t, 2H), 7.00 (s, 1H), 7.21 (s, 1H), and 7.43-7.51 (m, 3H), 7.85-7.90 (m, 2H).
Figure C0281867601141
Step 4.Under the standard hydrolysis condition, the ester of step 3 is converted into acid (non-enantiomer mixture 3: 2): ES-MS m/z 440 ((M+H) +); HPLC RT (min) 3.69; 1HNMR (d 6-DMSO) δ 0.83 (t, 3H), 2.34 (s, 3H), 2.92 (t, 2H), 4.21 (t, 2H), 7.00-7.02 (d, 1H), 7.12 (s, 0.24H), 7.21 (s, 0.37H), 7.47-7.48 (m, 3H), 7.87-7.90 (m, 2H).
Embodiment 27
Preparation 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1- Base } Valeric acid ethylester
Figure C0281867601142
The 15mL round-bottomed flask and the stirring rod of oven drying are cooled off under the Ar air-flow, to the 2-{5-[2-that wherein packs into (5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } ethyl acetate (0.070g, 0.17mmol), add 0.2mL THF subsequently.Solution after stirring is cooled to-78 ℃, and two (trimethyl silyl) Lithamides of dropping subsequently (the 1.0M hexane solution, 0.86mL, 0.86mmol).In case alkali adds and to finish, solution is stirred 1h at-78 ℃, then with syringe add iodo propane (0.142g, 0.86mmol).Reactant is slowly risen to room temperature and keeps 1h.In flask inclusion impouring 5mL ammonium chloride (aq), with ethyl acetate (3 * 10mL) extractions.Merge organic layer, use dried over sodium sulfate, vacuum concentration obtains 3.0mg (4.0% yield) colorless film dress thing.Product has: 1H NMR (300MHz, d6-acetone) δ 7.96 (dd, 8.1,1.5Hz, 2H), 7.48 (m, 3H), 6.99 (d, 8.4Hz, 1H), 6.79 (d, 2.7Hz, 1H), 6.70 (dd, 8.1,2.7Hz, 1H), 4.22 (t, 6.9Hz, 2H), 4.11 (q, 7.2Hz, 2H), 3.33 (q, 6.6Hz, 1H), 2.94 (t, 6.9Hz, 2H), 2.78 (m, 3H), 2.54 (m, 1H), 2.39 (s, 3H), 2.14 (m, 2H), 1.91 (m, 1H), 1.63 (qt, 10.2,3.9Hz, 2H), 1.21 (t, 7.2Hz, 3H), 0.852 (t, 7.5Hz, 3H); Mass spectrograph draws MH +448.2 (C 28H 33NO 4Calculate molecular weight=447.57).
Embodiment 28
Preparation 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1- Base } valeric acid
Figure C0281867601151
Obtain product with following feature according to the product of the method hydrolysis embodiment 27 of the foregoing description 2: 1H NMR (300MHz, d6-acetone); δ 7.96 (dd, 8.1,1.5Hz, 2H), 7.48 (m, 3H), 7.10 (d, 8.4Hz, 1H), 6.79 (d, 2.7Hz, 1H), 6.71 (dd, 8.1,2.7Hz, 1H), 4.22 (t, 6.9Hz, 2H), 3.40 (m, 1H), 2.91 (t, 6.9Hz, 2H), 2.74 (m, 1H), 2.58 (m, 1H), 2.39 (s, 3H), 2.26 (m, 1H), 2.11 (m, 1H), 1.95 (m, 2H), 1.84 (m, 1H), 1.62 (m, 2H), 0.859 (td, 6.9,1.5Hz, 3H); Mass spectrograph draws MH +420.1 (C 26H 29NO 4Calculate molecular weight=419.51).
Embodiment 29
Via 2-(6-bromo-5-hydroxyl-2,3-dihydro-1H-indenes-1-yl) methyl-butyrate Preparation 2-{6-bromo-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H- Indenes-1-yl } butyric acid
Figure C0281867601161
Step 1.(0.032mL, 0.60mmol) De diox (3mL) solution is cooled to 0 ℃ of 15min, after this adds 2-(5-hydroxyl-indane-1-yl)-methyl-butyrate (141mg, 0.60mmol) De diox (3mL) solution with bromine.Behind 5min, remove ice bath, reactant is at room temperature stirred 4h.Rotary evaporation removes and desolvates.Resistates by column chromatography purify (hexane that contains 8%EtOAc) obtain the single bromo intermediate (A) (145mg, 77%) of colorless oil and two bromo intermediates (B) (20mg).
A:R f=0.46 (4: 1 hexanes: EtOAc); GC-MS (+Cl): m/z=313 (M +); 1HNMR (DMSO-d 6): δ 0.840 (m, 3H), 1.511 (m, 2H), 1.905 (m, 1H), 2.091 (m, 1H), 2.410-2.793 (m, 3H), 3.212 (m, 1H), 3.505 and 3.512 (s, 3H), 6.713 and 6.753 (s, 1H), 7.034 and 7.274 (s, 1H), 9.932 and 9.934 (s, OH).
B:R f=0.30 (4: 1 hexanes: EtOAc); GC-MS (+Cl): m/z=393 (M +); 1HNMR (DMSO-d 6): δ 0.817 (m, 3H), 1.459-1.596 (m, 2H), 1.910 (m, 1H), 2.101 (m, 1H), 2.433-2.768 (m, 3H), 3.371 (m, 1H), 3.400 and 3.596 (s, 3H), 7.168 and 7.357 (s, 1H), 9.535 and 9.542 (s, OH).
Figure C0281867601171
Step 2.(118mg, DMF 0.38mmol) (3.8mL) solution add NaH, and (60% in mineral oil, 30mg) at 0 ℃ (A) to above step 1.Behind 1h, add the methanesulfonates of embodiment 26 steps 1 preparation.With mixture heating up to 50 ℃ 30h.The solution with water dilution is used ethyl acetate extraction three times then.Dried over sodium sulfate is used in the organic layer water and the salt water washing that merge then, concentrates.Resistates obtains product (63mg, 34%) by column chromatography purification (hexane that contains 10% ethyl acetate); R f=0.46 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=498 (MH +); 1H NMR (DMSO-d 6): δ 0.847 (m, 3H), 1.468 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H), 2.340 (s, 3H), 2.525-2.788 (m, 3H), 2.902 (m, 2H), 3.236 (m, 1H), 3.481 and 3.586 (s, 3H), 4.211 (m, 2H), 6.969 (s, 1H), 7.347 and 7.386 (s, 1H), 7.452 (m, 3H), 7.833 (m, 2H).
Step 3.Add 3N KOH (1mL) in the methanol solution of step 2 product (5.6mg), add THF subsequently and become clarification up to turbid solution.The mixture backflow is spent the night.Add dense HCl and regulate pH to 2, use ethyl acetate extraction then three times.Merge organic layer, drying concentrates then and obtains white solid (4mg).R f=0.18 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=484 (MH +); 1H NMR (DMSO-d 6): δ 0.832 (m, 3H), 1.468 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H), 2.405 (m, 1H), 2.788 (m, 2H), 2.904 (m, 2H), 3.015 (m, 1H), 3.136 and 3.138 (s, 3H), 4.209 (m, 2H), 6.987 and 7.344 (s, 1H), 6.972 and 7.251 (s, 1H), 7.487 (m, 3H), 7.882 (m, 2H).
Embodiment 30
Via 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-6-phenyl-2, the 3-dihydro- 1H-indenes-1-yl } methyl-butyrate
Preparation 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-6-phenyl-2, the 3-dihydro- 1H-indenes-1-yl } butyric acid
Step 1.With embodiment 29 step 2 products and Pd (PPh 3) 4THF (1.5mL) mixture at room temperature stir 30min.(13.2mg 0.108mmol) adds solution with 2N NaOH with phenyl-boron dihydroxide then.With mixture heating up to the 14h that refluxes.Allow solution cool off, dilute with water is used ethyl acetate extraction three times.Dried over sodium sulfate is used in the organic layer salt water washing that merges.Raw product obtains required product (8.6mg) by column chromatography purification (with the hexane wash-out that contains 5% ethyl acetate).R f=0.48 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=496 (MH +); 1H NMR (DMSO-d 6): δ 0.804 (m, 3H), 1.541 (m, 2H), 1.880 (m, 1H), 1.987 (m, 1H), 2.090 (s, 3H), 2.247-2.698 (m, 3H), 2.791 (m, 2H), 3.199 (m, 1H), 3.524 and 3.537 (s, 3H), 4.190 (m, 2H), 6.970 (s, 1H), 7.062 (s, 1H), 7.275 (m, 5H), 7.472 (m, 3H), 7.868 (m, 2H).
Figure C0281867601182
Step 2.According to the method described above the ester hydrolysis is obtained product: R f=0.16 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=482 (MH +); 1H NMR (DMSO-d 6): δ 0.923 (m, 3H), 1.504 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H), 2.188 (s, 3H), 2.334 (m, 2H), 2.432 (m, 2H), 2.539 (m, 1H), 2.625 (m, 1H), 4.287 (m, 2H), 7.059 (s, 1H), 7.160 (s, 1H), 7.351 (m, 5H), 7.544 (m, 3H), 7.971 (m, 2H).
Embodiment 31
Preparation 2-{6-(4-chloro-phenyl-)-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3- Dihydro-1H-indenes-1-yl } methyl-butyrate
Figure C0281867601191
With the product of embodiment 29 steps 2 preparations (71.4mg, 0.14mmol), sodium bicarbonate (14.3mg, 0.17mmol), 4-chlorophenylboronic acid (26.8mg, 0.17mmol) 20min that outgases of the mixture in glycol dimethyl ether (1.5mL) and water (0.4mL).Then with Pd (dppf) Cl 2Add solution.With mixture heating up to refluxing 2 days.Enriched mixture obtains required product (25mg) with column chromatography purification (hexane that contains 10%EtOAc).R f=0.51 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=530 (MH +); 1H NMR (DMSO-d 6): δ 0.841 (m, 3H), 1.557 (m, 2H), 1.888 (m, 1H), 1.987 (m, 1H), 2.146 (s, 3H), 2.247-2.698 (m, 3H), 2.791 (m, 2H), 3.214 (m, 1H), 3.487 and 3.5538 (s, 3H), 4.189 (m, 2H), 6.993 (s, 1H), 7.080 (s, 1H), 7.308 (s, 4H), 7.493 (m, 3H), 7.868 (m, 2H).
According to the method for the foregoing description 26-31, use the suitable initial feed preparation of alternate and characterize following compound:
Embodiment 32
2-{6-chloro-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1- Base } butyric acid
Figure C0281867601201
ESLC-MS:m/z=516 (MH +); 1H NMR (DMSO-d 6): δ 0.847 (m, 3H), 1.557 (m, 2H), 1.888 (m, 1H), 1.987 (m, 1H), 2.137 (s, 3H), 2.247-2.687 (m, 3H), 2.819 (m, 2H), 3.234 (m, 1H), 4.187 (m, 2H), 6.994 (s, 1H), 7.089 (s, 1H), 7.298 and 7.308 (m, 4H), 7.484 (m, 3H), 7.869 (m, 2H).
Embodiment 33
2-{6-methyl-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes- The 1-yl } methyl-butyrate
Figure C0281867601202
R f=0.23 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=434 (MH +); 1H NMR (DMSO-d 6): δ 0.804 (m, 3H), 1.522 (m, 2H), 1.830 (m, 1H), 1.987 (m, 1H), 2.037 (s, 3H), 2.335 (s, 3H), 2.410-2.550 (m, 3H), 2.901 (m, 2H), 3.146 (m, 1H), 3.507 (s, 3H), 4.163 (m, 2H), 6.777 (s, 1H), 6.939 (s, 1H), 7.483 (m, 3H), 7.875 (m, 2H).
Embodiment 34
2-{6-methyl-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes- The 1-yl } butyric acid
Figure C0281867601211
R f=0.31 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=420 (MH +); 1H NMR (DMSO-d 6): δ 0.827 (m, 3H), 1.508 (m, 2H), 1.828 (m, 1H), 1.987 (m, 1H), 2.017 (s, 3H), 2.333 (s, 3H), 2.410-2.550 (m, 3H), 2.894 (m, 2H), 3.146 (m, 1H), 4.116 (m, 2H), 6.773 (s, 1H), 6.942 (s, 1H), 7.467 (m, 3H), 7.880 (m, 2H).
Embodiment 35
2-[5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-6-(2-thienyl)-2, the 3-dihydro- 1H-indenes-1-yl] methyl-butyrate
Figure C0281867601212
R f=0.60 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=502 (MH +); 1H NMR (DMSO-d 6): δ 0.801 (m, 3H), 1.535 (m, 2H), 1.891 (m, 1H), 1.987 (m, 1H), 2.299 (s, 3H), 2.410-2.550 (m, 3H), 2.988 (m, 2H), 3.146 (m, 1H), 3.506 (s, 3H), 4.337 (m, 2H), 7.011-7.041 (m, 2H), 7.405-7.493 (m, 5H), 7.884 (m, 2H).
Embodiment 36
2-[5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-6-(2-thienyl)-2, the 3-dihydro- 1H-indenes-1-yl] butyric acid
Figure C0281867601221
R f=0.18 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=488 (MH +); 1H NMR (DMSO-d 6): δ 0.801 (m, 3H), 1.535 (m, 2H), 1.891 (m, 1H), 1.987 (m, 1H), 2.299 (s, 3H), 2.410-2.550 (m, 3H), 2.988 (m, 2H), 3.146 (m, 1H), 4.337 (m, 2H), 7.078 (m, 2H), 7.472 (m, 5H), 7.896 (m, 2H).
Embodiment 37
2-{4,6-two bromo-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H- Indenes-1-yl } methyl-butyrate
Figure C0281867601222
R f=0.35 (4: 1 hexanes: EtOAc); ESLC-MS:m/z=578 (MH +); 1H NMR (DMSO-d 6): δ 0.847 (m, 3H), 1.468 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H), 2.350 (s, 3H), 2.407-2.788 (m, 3H), 2.982 (m, 2H), 3.225 (m, 1H), 3.480 and 3.588 (s, 3H), 4.145 (m, 2H), 7.276 (s, 1H), 7.458 (m, 3H), 7.866 (m, 2H).
Embodiment 38
2-{4,6-two bromo-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H- Indenes-1-yl } butyric acid
R f=0.17 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=564 (MH +); 1H NMR (DMSO-d 6): δ 0.847 (m, 3H), 1.468 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H), 2.361 (s, 3H), 2.414-2.781 (m, 3H), 2.995 (m, 2H), 3.123 (m, 1H), 4.125 (m, 2H), 7.345 (s, 1H), 7.437 (m, 3H), 7.886 (m, 2H).
Embodiment 39
Via 2-(6-ethanoyl-5-methoxyl group-2,3-dihydro-1H-indenes-1-yl) methyl-butyrate Preparation 2-{6-ethanoyl-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2, the 3-dihydro -1H-indenes-1-yl } butyric acid
Figure C0281867601232
Step 1.At 0 ℃ to aluminum chloride (103mg, 0.78mmol) methylene dichloride (2.5mL) solution in add Acetyl Chloride 98Min. (0.044mL, 0.63mmol), Dropwise 5-methoxyl group-2 subsequently, 3-dihydro-1H-indenes-1-base-methyl-butyrate (130mg, methylene dichloride 0.52mmol) (2.7mL) solution.Mixture is stirred 15min at 0 ℃.Remove ice bath, 16h at room temperature stirs the mixture.Mixture is poured on ice, adds 4 dense HCl.Twice of dichloromethane extraction of this mixture.The organic layer water, 0.05N NaOH and the water washing that merge.Dry organic layer concentrates, then with flash chromatography purification (10%EtOAc: hexane) obtain required product (103mg, 68%).R f=0.28 (4: 1 hexanes: EtOAc); GC-MS (+Cl): m/z=291 (M +); 1H NMR (DMSO-d 6): δ 0.840 (m, 3H), 1.536 (m, 2H), 1.876 (m, 1H), 2.108 (m, 1H), 2.505 (s, 3H), 2.521 (m, 1H), 2.760-2.889 (m, 2H), 3.236 (m, 1H), 3.511 and 3.589 (s, 3H), 3.836 (s, 3H), 7.012 and 7.253 (s, 1H), 7.440 (s, 1H).
Figure C0281867601241
Step 2.(238mg adds step 1 product (103mg, methylene dichloride 0.35mmol) (2mL) solution to aluminum chloride in methylene dichloride 1.77mmol) (1mL) solution.Mixture is cooled to 0 ℃ of 5min, slowly add then EtSH (0.13mL, 1.77mmol).Mixture is stirred 4.5h in this temperature.Then mixture is poured on the frozen water, stirs 10min, use twice of dichloromethane extraction.The organic layer that merges washes with water, uses dried over sodium sulfate, concentrates then to obtain product (86mg, 89%).R f=0.51 (4: 1 hexanes: EtOAc); GC-MS (+Cl): m/z=276 (M +); 1H NMR (DMSO-d6): δ 0.841 (m, 3H), 1.574 (m, 2H), 1.888 (m, 1H), 2.094 (m, 1H), 2.585 (s, 3H), 2.639 (m, 1H), 2.729-2.847 (m, 2H), 3.244 (m, 1H), 3.513 and 3.628 (s, 3H), 6.774 and 7.503 (s, 1H), 6.792 and 7.715 (s, 1H), 12.117 and 12.143 (s, 1H).
Figure C0281867601242
Step 3.With the hydroxyl indeneacetic acid ester of step 2 and the methanesulfonates coupling of embodiment 26 steps 2.ESLC-MS：m/z＝462(MH +)；
Figure C0281867601243
Step 4.Product according to the above-mentioned hydrolysing step of mode similarly 3 obtains product: R f=0.08 (2: 1 hexanes: EtOAc); ESLC-MS:m/z=448 (MH +); 1H NMR (DMSO-d 6): δ 0.848 (m, 3H), 1.468 (m, 2H), 1.812 (m, 1H), 2.146 (m, 1H), 2.305 (s, 3H), 2.368 (s, 3H), 2.405 (m, 1H), 2.788 (m, 2H), 2.971 (m, 2H), 3.015 (m, 1H), 4.332 (m, 2H), 7.039 and 7.441 (s, 1H), 7.446 (s, 1H), 7.465 (m, 3H), 7.875 (m, 2H).
Use the combination and the suitable initial feed of alternate of above-mentioned steps to prepare all cpds described below.
Embodiment 40
2-{5-[2-(2,5-phenylbenzene-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } butyric acid Methyl esters
Figure C0281867601251
Yield: 0.09g, 46%; 1H NMR (CDCl 3, 400MHz) δ 0.83-0.93 (t, 3H), 1.55-1.78 (m, 2H), and 1.87-1.97 (m, 1H), 2.10-2.22 (m, 1H), and 2.44-2.52 (m, 1H), 2.67-2.80 (m, 1H), and 2.81-2.93 (m, 1H), 3.21-3.29 (m, 1H), and 3.23-3.33 (t, 2H), 3.62 (s, 3H), and 4.34-4.43 (t, 2H), 6.66-6.72 (m, 1H), 6.76 (s, 1H), 7.05-7.14 (d, 1H), and 7.33-7.39 (t, 1H), 7.43-7.51 (m, 5H), 7.78-7.84 (d, 2H), and 8.06-8.12 (m, 2H).
Embodiment 41
2-{5-[2-(2,5-phenylbenzene-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } butyric acid
Figure C0281867601252
Yield: 0.07g, 70%; 1H NMR (CDCl 3, 400MHz) δ 0.85-0.98 (m, 3H), 1.23-1.47 (m, 1H), 1.57-1.78 (m, 1H), and 1.88-2.07 (m, 1H), 2.12-2.27 (m, 1H), 2.43-2.56 (m, 1H), and 2.68-2.97 (m, 2H), 3.27-3.35 (t, 2H), 3.42-3.50 (m, 1H), and 4.34-4.41 (t, 2H), 6.66-6.73 (d, 1H), 6.77 (s, 1H), and 7.02-7.16 (d, 1H), 7.34-7.40 (t, 1H), 7.43-7.52 (m, 5H), and 7.78-7.83 (d, 2H), 8.05-8.12 (m, 2H).
Embodiment 42
2-{5-[2-(5-sec.-propyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } Methyl-butyrate
Figure C0281867601261
Yield: 0.09g, 45%; 1H NMR (CDCl 3, 400MHz) δ 0.78-0.96 (t, 3H), 1.26-1.32 (d, 6H), and 1.51-1.62 (m, 1H), 1.64-1.75 (m, 1H), and 1.81-1.93 (m, 1H), 2.07-2.21 (m, 1H), and 2.40-2.51 (m, 1H), 2.65-2.75 (m, 1H), and 2.77-2.98 (m, 1H), 2.91-2.98 (t, 2H), and 3.09-3.16 (m, 1H), 3.21-3.28 (m, 1H), 3.62 (s, 3H), 4.10-4.17 (t, 2H), and 6.60-6.68 (d, 1H), 6.72 (s, 1H), and 7.01-7.13 (d, 1H), 7.33-7.45 (m, 3H), and 7.94-8.00 (d, 2H).
Embodiment 43
2-{5-[2-(5-sec.-propyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } Butyric acid
Yield: 0.08g, 97%; 1H NMR (CDCl 3, 400MHz) δ 0.91-0.98 (t, 3H), 1.30-1.36 (d, 6H), 1.58-1.79 (m, 2H), and 1.89-2.05 (m, 1H), 2.12-2.27 (m, 1H), 2.44-2.57 (m, 1H), and 2.69-2.80 (m, 1H), 2.83-2.96 (m, 1H), 2.97-3.02 (t, 2H), and 3.10-3.21 (m, 1H), 3.24-3.32 (m, 1H), 4.14-4.21 (t, 2H), 6.63-6.71 (d, 1H), 6.75 (s, 1H), 7.04-7.16 (d, 1H), and 7.36-7.45 (m, 3H), 7.94-8.00 (d, 2H).
Embodiment 44
2-{5-[2-(5-ethyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenyl } butyric acid Methyl esters
Figure C0281867601271
Yield: 0.14g, 60%; 1H NMR (CDCl 3, 400MHz) δ 0.85-0.91 (t, 3H), 1.25-1.35 (t, 3H), 1.58-1.77 (m, 2H), and 1.85-1.97 (m, 1H), 2.10-2.22 (m, 1H), 2.44-2.64 (m, 2H), and 2.68-2.80 (q, 2H), 2.82-2.93 (m, 1H), 2.95-3.01 (t, 2H), 3.25-3.34 (m, 1H), 3.62 (s, 3H), 4.16-4.25 (t, 2H), 6.66-6.71 (d, 1H), 6.75 (s, 1H), 7.08-7.14 (d, 1H), and 7.38-7.46 (m, 3H), 7.95-8.01 (m, 2H).
Embodiment 45
2-{5-[2-(5-ethyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } fourth Acid
Figure C0281867601272
Yield: 0.05g, 60%; 1H NMR (CDCl 3, 400MHz) δ 0.85-0.98 (m, 3H), 1.21-1.33 (m, 3H), 1.37-1.54 (m, 1H), and 1.56-1.78 (m, 2H), 1.87-2.29 (m, 2H), 2.45-2.60 (m, 1H), and 2.69-2.79 (q, 2H), 2.85-2.95 (m, 1H), 2.96-3.01 (t, 2H), and 3.27-3.49 (m, 1H), 4.14-4.23 (t, 2H), 6.65-6.71 (d, 1H), 6.75 (s, 1H), 7.03-7.17 (d, 1H), and 7.38-7.46 (m, 3H), 7.95-8.01 (d, 2H).
Embodiment 46
2-{5-[2-(2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenyl } methyl-butyrate
Yield: 0.18g, 80%; 1H NMR (CDCl 3, 400MHz) δ 0.82-0.92 (t, 3H), 1.56-1.66 (m, 1H), and 1.67-1.77 (m, 1H), 1.88-1.99 (m, 1H), and 2.12-2.23 (m, 1H), 2.43-2.52 (m, 1H), and 2.68-2.81 (m, 1H), 2.84-2.97 (m, 1H), and 3.02-3.11 (t, 2H), 3.25-3.33 (m, 1H), 3.63 (s, 3H), 4.21-4.30 (t, 2H), and 6.69-6.74 (d, 1H), 6.79 (s, 1H), and 7.11-7.16 (d, 1H), 7.41-7.47 (m, 3H), 7.55-7.58 (m, 1H), and 7.99-8.05 (m, 2H).
Embodiment 47
2-{5-[2-(2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } butyric acid
Figure C0281867601282
Yield: 0.07g, 46%; 1H NMR (CDCl 3, 400MHz) δ 0.84-1.01 (m, 3H), 1.36-1.51 (m, 1H), 1.59-1.81 (m, 1H), and 1.88-2.00 (m, 1H), 2.11-2.29 (m, 1H), 243-2.64 (m, 1H), and 2.68-2.81 (m, 1H), 2.82-3.00 (m, 2H), 3.02-3.11 (t, 2H), and 3.23-3.37 (m, 1H), 4.17-4.28 (t, 2H), 6.66-6.74 (d, 1H), 6.78 (s, 1H), 7.04-7.19 (m, 1H), 7.39-7.47 (m, 2H), 7.55 (s, 1H), 7.98-8.05 (m, 2H).
Embodiment 48
2-(5-{2-[2-(2,3-dihydro-1-cumarone-6-yl)-5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group }- 2,3-dihydro-1H-indenes-1-yl) methyl-butyrate
Figure C0281867601291
Yield: 0.17g, 58%; 1H NMR (CDCl 3, 400MHz) δ 0.86-0.97 (t, 3H), 1.41-1.53 (m, 1H), 1.61-1.77 (m, 1H), 1.92-2.01 (m, 1H), 2.04-2.20 (m, 1H), 2.40 (s, 3H), 2.49-2.56 (m, 1H), 2.71-2.92 (m, 2H), 3.93-3.00 (t, 2H), 3.21-3.32 (t, 2H), 3.34-3.49 (m, 1H), 3.75 (s, 3H), 4.18-4.24 (t, 2H), 4.54-4.70 (t, 2H), 6.70-6.76 (d, 1H), 6.79 (s, 1H), 6.82-6.89 (d, 1H), 6.92-7.01 (d, 1H), 7.75-7.80 (d, 1H), 7.87 (s, 1H).
Embodiment 49
2-(5-{2-[2-(2,3-dihydro-1-cumarone-6-yl)-5-methyl isophthalic acid, 3-oxazole-4-yl] oxyethyl group }- 2,3-dihydro-1H-indenes-1-yl) butyric acid
Figure C0281867601292
Yield: 0.10g, 99%; 1H NMR (CDCl 3, 400MHz) δ 0.90-1.04 (t, 3H), 1.41-1.54 (m, 1H), and 1.60-1.76 (m, 1H), 1.83-1.97 (m, 1H), and 2.12-2.23 (m, 1H), 2.35 (s, 3H), and 2.48-2.60 (m, 1H), 2.69-2.90 (m, 2H), and 2.92-3.01 (t, 2H), 3.18-3.28 (t, 2H), and 3.39-3.50 (m, 1H), 4.08-4.12 (t, 2H), and 4.46-4.64 (t, 2H), 6.76-6.71 (d, 1H), 6.73 (s, 1H), 6.77-6.84 (d, 1H), and 7.01-7.09 (d, 1H), 7.71-7.78 (d, 1H), 7.83 (s, 1H).
Embodiment 50
Via [5-(benzyloxy)-2,3-dihydro-1H-indenes-1-subunit] (oxyethyl group) ethyl acetate The preparation oxyethyl group 5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group] and-2,3-dihydro-1H- Indenes-1-yl } acetate
Figure C0281867601301
Step 1.At-78 ℃ of 50mL THF solution with LDA (with 11mmol DIA and 11mmol BuLi preparation) adding 2-ethoxy acetate (10mmol), stir 1h, add TMSCl (30mmol) then.Vacuum concentrated mixture is directly used in next step with it and need not to purify again.
Figure C0281867601302
Step 2.Slowly add TiCl at-78 ℃ of methylene dichloride (5mL) with 5-benzyloxy-1-indone 4Methylene dichloride (10mL) solution, stir 10min at-60 ℃, be cooled to-78 ℃ then.Slowly add methylene dichloride (5mL) solution of step 1 product, stir 10min.Reactant saturated potassium carbonate quencher is filtered, and uses ethyl acetate extraction, uses dried over sodium sulfate.Column chromatography is handled and is obtained the colorless oil product.LC-MS MH +＝353.1，RT＝4.00min；NMR(CDCl 3，400MHz)δ7.9(1H，d)，7.25(5H，m)，6.78(2H，m)，4.93(2H，s)，4.15(2H，q)，3.75(2H，q)，3.05(2H，m)，2.85(2H，m)，1.22(6H，m)
Figure C0281867601311
Step 3.Similar approach according to embodiment 13 step 4-8 adopts step 2 product as initial feed, prepares required end product and sign: LC-MS[MH +]=422.2, RT=3.25min; NMR (CDCl 3, 400MHz) δ 8.26 (1H, d), 7.55 (2H, m), 7.16 (2H, d), 6.70 (3H, m), 4.16 (2H, q), 3.63 (2H, t) 3.5 (2H, m), 3.30 (1H, m), 3.20 (1H, m), 2.50 (3H, s), 1.10 (3H, m).
Embodiment 51
Via 2-(4-methyl-2-phenyl-1,3-oxazole-5-yl) ethanol Preparation 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1- Base } butyric acid
Figure C0281867601312
Step 1.At room temperature, sodium hydroxide (8.98g, and adding DL-L-Ala in water 224.49mmol) (112.25mL) solution (10g, 112.25mmol).With gained solution 75 ℃ of heating, slowly add Benzoyl chloride (15.77g, 112.25mmol).Reactant is heated 30min, be cooled to 0 ℃ with ice bath.Add dense HCl and regulate pH to 1, leach white solid by sintered glass funnel then, spend the night with Vanadium Pentoxide in FLAKES vacuum-drying.Do not need to purify.Obtain to be the N-benzoyl L-Ala of white solid (19.6g, 90.4% yield). 1H NMR(DMSO-d 6)δ12.61(s br，1H)，8.64(d，1H)，7.87-7.85(m，2H)，7.52-7.43(m，3H)，4.40(q，1H)，1.39(d，3H)。
Figure C0281867601321
Step 2.In first flask, with N-benzoyl L-Ala (2g 10.35mmol) is dissolved in THF (20mL), add carbonyl dimidazoles (CDI) (1.84g, 11.39mmol).The gained mixture at room temperature stirs 1h, is cooled to-78 ℃.In second flask, (3.83g, THF 43.48mmol) (40mL) solution is cooled to-78 ℃, adds the LDA (24.3mL, 48.51mmol, the THF solution of 2M) that is cooled to-78 ℃ in advance with ethyl acetate.Gained solution stirs 30min at-78 ℃, and the enol lithium that produces is joined in first flask with sleeve pipe.Gained white soup compound stirs 30min at-78 ℃, rises to-10 ℃.Reactant NH 4The saturated aqueous solution quencher of Cl.Separate each phase, organic dried over mgso of using, removal of solvent under reduced pressure.Raw product is directly used in next step and need not to purify again.Obtain white solid 4-(benzoyl-amido)-3-oxopentanoic acid ethyl ester (2.6g, 95.5% yield) thus.ES-MS m/z263.4 ((MH) +); HPLC RT (min) 1.53; 1H NMR (acetone-d 6) δ 8.13 (s br, 1H), 7.93-7.91 (m, 2H), 7.58-7.43 (m, 3H), 4.72 (m, 1H), 4.19-4.01 (q, 2H), 3.67 (s, 2H), 1.47 (d, 3H), 1.15 (t, 3H).
Step 3.At room temperature, (0.6g adds POCl in DMF 2.28mmol) (4mL) crude mixture to 4-(benzoyl-amido)-3-oxopentanoic acid ethyl ester 3(1.04g, 6.84mmol).Gained solution at 90 ℃ of heating 1h, is cooled to room temperature then, 30min in the impouring ice.Aqueous solution is carefully added saturated aqueous solution of sodium bicarbonate.Separate each phase with EtOAc, the organic extract liquid dried over mgso of merging, removal of solvent under reduced pressure.Raw product Biotage pillar purification (using the solvent gradient of 0-50%EtOAc/ hexane).Obtain little yellow oily (4-methyl-2-phenyl-1,3-oxazole-5-yl) ethyl acetate (0.269g 48% yield) thus.ES-MS m/z246.2((MH) +)；HPLC RT(min)2.77； 1H NMR(CDCl 3)δ8.01-7.98(m，2H)，7.45-7.41(m，3H)，4.20(q，2H)，3.71(s，2H)，2.21(s，3H)，1.28(t，3H)。
Figure C0281867601331
Step 4.At room temperature, (0.922g, THF 3.76mmol) (6mL) solution adds LiBH with (4-methyl-2-phenyl-1,3-oxazole-5-yl) ethyl acetate 42M/THF (9.41mL, 4.70mmol).Reactant at room temperature stirred spend the night, handle up to pH 7 with 2N HCl then.Removal of solvent under reduced pressure THF adds EtOAc, separates each phase then.The organic extract liquid dried over mgso that merges, the vacuum concentration solvent.Raw product is with Biotage purify (using 10-100%EtOAc/ hexane solvent mixture gradient).Obtain colorless oil 2-(4-methyl-2-phenyl-1,3-oxazole-5-yl) ethanol (0.193g, 25% yield).ES-MS m/z 204.2 (MH) +); HPLC RT (min) 2.02; 1H NMR (acetone-d 6) δ 7.98-7.95 (m, 2H), 7.52-7.42 (m, 3H), 3.95 (s br, 1H), 3.82 (t, 2H) m, 2.90 (t, 2H), 2.13 (s, 3H).
Figure C0281867601332
Step 5.With DEAD (0.84mL, THF 5.28mmol) (1.5mL) solution slowly adds step 3 product (4.95mmol), 5-hydroxyl-2,3-dihydro-indenes-1-base-2-methyl-butyrate (0.78g, 3.3mmol), PPh 3(1.4g, THF 5.28mmol) (13mL) solution.Mixture at room temperature stirred spend the night.Filtering mixt, dried over sodium sulfate is used in water, salt water washing, concentrates then.Column chromatography is handled and is obtained the colorless oil product.LC-MS[C 26H 29NO 4H] +＝420.4，RT＝4.00min； 1H NMR(CDCl 3)δ7.9(2H，d)，7.45(2H，dd)，7.1(d)，6.6-6.8(3H，m)，4.2(2H，t)，3.62(3H，s)，3.3(1H，m)，3.15(2H，t)，2.6-3.0(2H，m，br)，2.5(1H，m)，2.21(3H，s)，1.95(1H，m)，1.56-1.6(3H，br，m)，0.88(3H，t)。
Figure C0281867601333
Step 6.(0.5mL 3N) adds step 4 product (42mg, THF/MeOH 0.1mmol) (1mL, THF: MeOH 8: 2) solution with KOH.Mixture is stirred 6h at 70 ℃, then cooling.With 1N HCl with pH regulator to 4.(3 * 2mL) extract mixture with ethyl acetate.The organic layer dried over sodium sulfate that merges, vacuum concentration.Column chromatography (2: 8/ hexanes: ethyl acetate) obtain white solid product (33mg, 81%).LC-MS[C 25H 27NO 4H] +＝406.3，RT＝3.37min； 1H NMR(CDCl 3)：δ8.0(2H，d)，7.45(2H，dd)，7.15(1H，d)，6.7-6.8(3H，m)，4.2(2H，t)，3.3(1H，m)，3.15(2H，t)，2.6-3.0(2H，m，br)，2.5(1H，m)，2.21(3H，s)，1.95(1H，m)，1.56-1.6(3H，br，m)，0.88(3H，t)
Use the method and the suitable initial feed of alternate of the foregoing description 51, prepare similarly and characterize following compound.
Embodiment 52
LC-MS[C 26H 29NO 4H] +＝420.3，RT＝3.52min； 1H NMR(CDCl 3)：δ7.87(2H，d)，7.25(2H，dd)，7.1(1H，d)，6.6-6.8(3H，m)，4.2(2H，t)，3.45(1H，m)，3.30(1H，m)，3.15(2H，t)，2.7-3.0(2H，m，br)，2.5(1H，m)，2.4(3H，s)1.95(1H，m)，1.56-1.60(3H，br，m)，0.88(3H，t)
Embodiment 53
2-{5-[2-(4-methyl-2-propyl group-1,3-oxazole-5-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } fourth Acid
Figure C0281867601342
LC-MS[C 22H 29NO 4H] +＝372.3，RT＝3.16min； 1H NMR(CDCl 3)：δ7.1(1H，d)，6.6(2H，d)，4.2(2H，t)，3.3(1H，m)，3.3(1H，m)，2.8(2H，t)，2.7(1H，m)，2.6(2H，t)，2.4(2H，m)，2.2(3H，s)，2.0-1.8(2H，br，m)，0.88(3H，t)
Use method and the suitable initial feed of alternate of the foregoing description 1-53, prepare the formula Ia compound of following table 3 similarly.
Table 3
The preparation embodiment of formula (Ia) compound
Figure C0281867601351
Ex. No. R R 1 R 2 R 3 R 4 R 5 X LC-MS[M+H] +Or NMR
54 H Et H Me PhOCH 2- H O 436.2
55 H Et H Me PhCH 2- H O 420
56 H H H Me Ph H O 378.2
57 Me Ph(CH 2) 3- H Me Ph H O 3.45/3.52(t，3H)， 4.10(t，2H)，7.3(m， 3H)，7.83(d，2H)
58 Et EtO 2C- H Me Ph H O 478.2
59 Et Et H Me Ph H O 434.3
60 H MeO H Me Ph H O 3.30(s，3H)，4.04(d， 1H)，7.98(m，2H)
61 Et EtO H Me Ph H O 450.3
62 H CF 3CH 2- H Me Ph H O 2.51(s，3H)，4.36 (m，2H)，8.32(m， 2H)
63 Et CF 3CH 2- H Me Ph H O 1.18(t，3H)，4.21(t， 2H)，7.98(d，2H)
64 Me cyc-Pr H Me Ph H O 432.3
65 H cyc-Pr H Me Ph H O 0.02(m，1H)，0.12 (m，1H)，4.18(m， 2H)，7.94(m，2H)
Figure C0281867601361
Ex. No. R R 1 R 2 R 3 R 4 R 5 X LC-MS[M+H] +Or NMR
88 H Et H Me 4-MeO-Ph H O 436.1
89 H Et H Me 4-i-Pr-Ph H O 448.2
90 H Et H Me 4-F-PhCH 2- H O 438.3
91 H Et H Me 4-F-Ph H O 424.3
92 H Et H Me 4-Et-Ph H O 434.3
93 H Et H Me 4-Cl-PhOCH 2- H O 470.2
94 H Et H Me 4-Cl-Ph H O 440
95 Me Et H Me 4-Cl-Ph H S 470.3
96 Me Et H Me 4-Cl-Ph H S 470.3
97 H Et H Me 4-CF 3-Ph H S 490.3
98 Me Et H Me 4-CF 3-Ph H S 504.3
99 H Et H Me 4-CF 3-Ph H O 474.3
100 H Et H Me 4-(n-Bu)-Ph H O 462.3
101 H Et H Me 4-(t-Bu)-Ph H O 462.3
102 H Et H Me 3-Me-Ph H O 420.4
103 H Et H Me 3-MeO-Ph H O 436.3
104 H Et H Me The 3-Me-5-isoxazolyl H O 411.3
105 H Et H Me 3-F-Ph H O 424.2
106 H Et H Me 3-F-4-Me-Ph H O 438.2
107 H Et H Me 4-F-3-Me-Ph H O 438.3
108 Me Et H Me 3-Cl-Ph H S 470.3
109 H Et H Me 3-Cl-Ph H O 440.3
110 H Et H Me 3-Cl-Ph H S 456.3
111 H Et H Me 3-CF 3-Ph H O 474.2
112 H Et H Me 3，5-(CF 3) 2-Ph H O 542.1
113 H Et H Me 3，4-Me 2-Ph H O 434.3
114 H Et H Me 3，4-Cl 2-Ph H O 474.2
115 H Et H Me 2，3-Cl 2-Ph H O 474.1
116 H Et H Me 3，4-(MeO) 2-Ph H O 466.3
Figure C0281867601381
Embodiment 129
Preparation (5-methoxyl group-2,3-dihydro-1H-indenes-1-subunit) ethyl acetate
Figure C0281867601382
5-melonia indone (150g, add in anhydrous tetrahydro furan 0.91mol) (4.5L) solution zinc (30 orders, 103.64g, 1.59mol) and cupric chloride (I) (4.53g, 0.045mol).Suspension is stirred backflow 15min under argon atmospher; (133mL 1.18mol) adds in the backflow mixture with about 1/4 ethyl bromoacetate in the mode of slow dropping.In cooling and after at room temperature stirring is spent the night, the required product of TLC alleged occurrence illustrates to have formed reactive zinc class material.Drip remaining ethyl bromoacetate; Observe heat release (internal temperature rises to 35 ℃).Behind 4h, TLC confirms complete reaction.After at the bottom of solid precipitation arrives flask, with liquid siphon pipe sucking-off, the only remaining solid that just floods on a small quantity.Reload 5-melonia indone (157.6g, 1.86mol altogether), anhydrous tetrahydro furan (4.5L) and zinc (80.92g, 2.73mol altogether) in the flask.Dripping bromine ethyl acetate (140mL, 2.36mol altogether).Observe heat release (internal temperature rises to 35 ℃).After mixture under agitation was cooled to room temperature, TLC confirmed complete reaction.Allow solid precipitation, with siphon pipe sucking-off liquid.Reaction soln to the volume that vacuum concentration merges is about 2L.In the 1N aqueous hydrochloric acid (cooling off with frozen water) with liquid impouring capacity, making pH is 1 then.(2 * 1L, 1 * 500mL) extracts product with ethyl acetate.Dried over sodium sulfate is used in the extraction liquid water that merges, salt solution (each 1L) washing, filters, and vacuum concentration obtains scarlet oily matter then, solidifies (438.3g gradually; Theoretical yield=432g). 1HNMR(CDCl 3)：δ7.5(d，1H)，6.8(m，2H)，6.2(t，1H)，4.2(q，2H)，3.8(s，3H)，3.3(m，2H)，3.0(t，2H)，1.3(t，3H)。MS(Cl)m/z 233[M+H] +。
Embodiment 130
Preparation (5-methoxyl group-2,3-dihydro-1H-indenes-1-yl) ethyl acetate
Figure C0281867601391
Embodiment 129 raw products are dissolved in dehydrated alcohol (2.6L), under the 40psi nitrogen atmosphere, carry palladium (21.6g) hydrogenation with 10% carbon.Filter by Celite, concentrated filtrate obtains 433.3g brown oil (yields 99% of 2 steps). 1H NMR(CDCl 3)：δ7.1(dd，1H)，6.8(d，1H)，6.7(dd，1H)，4.2(q，2H)，3.8(s，3H)，3.5(m，1H)，2.9(m，2H)，2.7(dd，1H)，2.4(m，2H)，1.7(m，1H)，1.3(t，3H)。MS(Cl)m/z 235[M+H] +。
Embodiment 131
Preparation (5-methoxyl group-2,3-dihydro-1H-indenes-1-yl) acetate
Figure C0281867601392
(416g adds NaOH (142g, 1.5L aqueous solution 3.54mol) to the crude ester of embodiment 130 preparations in 1LEtOH solution 1.77mol).Muddy reaction mixture is heated to backflow, and color becomes scarlet during this period, and it is even that reactant becomes.Behind 1h, allow reactant be cooled to room temperature, EtOH is removed in decompression.(3 * 500mL) washings are acidified to pH～4 with dense HCl behind the formation oily resistates to the alkalescence water layer with ether.(4 * 500mL) extract mixture with ether.The extraction liquid water that merges (2 * 300mL), the salt water washing, use dried over sodium sulfate then.Filter and solvent evaporated under reduced pressure, obtain yellow solid title compound (305g, 83%) after vacuum-drying is spent the night. 1H NMR(CDCl 3)δ7.34(d，1H)，6.71(s，1H)，6.65(dd，1H)，3.71(s，3H)，3.47(m，1H)，2.80(m，3H)，2.35(m，2H)，1.71(m，1H)。MS(Cl)m/z 207[M+H] +。
Embodiment 132
Preparation [(1S)-and 5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] acetate
Figure C0281867601401
Under room temperature, stirring, the acid of embodiment 131 preparations (341.0g, and dropping (S)-(-)-Alpha-Methyl benzylamine in 8.2L reagent grade acetone solution 1.65mol) (223.8mL, 1.74mol).Form dense white precipitate during this period.Add 500mL acetone again, continue to stir 1h.Solid collected by filtration is used the 300mL washing with acetone, the drying of bleeding then.Again with solid suspension in acetone (8.2L), heat to refluxing up to all solid dissolvings.With the slow cool overnight of solution, form white precipitate during this period.Suspension is cooled to 0 ℃, filters solid 500mL washing with acetone then.After suction dried, confirm 95%ee by the HPLC analytic sample.Repeat above-mentioned recrystallization process with 6.7L acetone.HPLC analyzes and confirms 99%ee.After suction dried, obtain 192g salt.Salt suspension in 2L EtOAc and 1L 1N HCl solution, is vibrated in separating funnel, so the salt dissolving.Separate organic layer, with 1N HCl (500mL), water (2 * 300mL) and the salt water washing, use dried over sodium sulfate then.Solvent evaporated under reduced pressure obtains very fast solidified oily matter.After vacuum-drying, obtain Off-white solid title product (120.5g, 35%). 1H NMR(CDCl 3)δ7.10(d，1H)，6.79(d，1H)，6.73(dd，1H)，3.79(s，3H)，3.55(m，1H)，2.89(m，2H)，2.79(dd，1H)，2.46(dd，1H)，2.43(m，1H)，1.80(m，1H)。MS(ESI)m/z 207[M+H] +。
Embodiment 133
Preparation [(1S)-and 5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] acetate
Figure C0281867601411
As another program of embodiment 132, title compound also can prepare by enzyme process.Therefore, crude ester (500.0g, the 2.13mol of embodiment 130 preparations; It is 87% that HPLC records purity) (pH 7.0, and disposable adding Amano Lipase PS (150g) 0.05M) and in the turbid mixture in the 2.5L deionized water at room temperature fully stirs the mixture and spends the night at 1L reagent grade acetone, 2.5L phosphate buffered saline buffer.HPLC analyzes aliquots containig (dissolving aliquots containig after-filtration makes even aliquots containig in IPA) and confirms a peak corresponding to unreacted R-ester, and another peak is corresponding to required S-acid.Show trace S-ester and R-acid.In the disposable adding reactant of 2N HCl (500mL guarantees that pH is～2), stir 20min.Filtering mixt, solid use successively EtOAc (2 * 500mL), water (500mL) washing.The filtrate that merges is further with 1L EtOAc dilution, with each layer vigorous stirring together.Stop to stir, separate each layer.Milk sap occurs, but stir destruction after can adding solid NaCl.Shift out water layer, use EtOAc (3 * 1L) extractions in the same manner.The organic extract liquid that merges successively water (4 * 500mL), the salt water washing.Gained organic layer 5%Na 2CO 3Solution (8 * 500mL) extractions.HPLC analyzes organic layer and confirms not have the acid of S-enantiomer.The Na that merges 2CO 3(2 * 1L) washings add 2N HCl and are acidified to pH～2 extraction liquid then with EtOAc.Be settled out white solid, follow CO 2Discharge.(3 * 1L) extract mixture with EtOAc.The extraction liquid water that merges (2 * 1L) and the salt water washing, use dried over sodium sulfate then.HPLC analyzes this solution and confirms product 98%ee.Solvent evaporated under reduced pressure obtains very fast solidified oily matter.After vacuum-drying, obtain Off-white solid title product (172.9g).This product ebullient hexane (8.8L) recrystallization.After cool overnight, filter and collect light yellow spicule, with hexane (200mL) washing, the drying of bleeding then.The light yellow needle-like title product of acquisition after vacuum-drying (146.9g, 38%, in rough initial ester). 1H NMR result is the same.
Embodiment 134
Preparation [(1S)-and 5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] ethyl acetate
Under room temperature, argon atmospher, the acid of embodiment 132 or 133 preparations (305g, and dropping chlorine trimethyl silane in the anhydrous EtOH solution of 4.8L 1.48mol) (413mL, 3.25mol).Temperature has approximately risen 5 ℃ during adding.Reaction stirred is spent the night.Reduction vaporization EtOH obtains the two-phase liquid mixture.It with the dilution of 500mL frozen water, is used EtOAc (2 * 750mL) extractions then.The extraction liquid that merges successively water (3 * 300mL), saturated sodium bicarbonate (200mL) washing.Water (300mL), salt water washing are once used dried over sodium sulfate to organism successively again.After removing the also vacuum-drying of desolvating, obtain light yellow oily title compound (354g, 102%). 1H NMR(CDCl 3)δ7.07(d，1H)，6.78(d，1H)，6.71(dd，1H)，4.18(q，2H)，3.78(s，3H)，3.52(m，1H)，2.89(m，2H)，2.72(dd，1H)，2.37(o，2H)，1.74(m，1H)，1.28(t，3H)。MS(Cl)m/z 235[M+H] +。
Embodiment 135
Preparation [(1S)-and 5-hydroxyl-2,3-dihydro-1H-indenes-1-yl] ethyl acetate
Under argon atmospher, (346g adds AlCl in the 4.2L methylene dichloride cold soln (ice-water bath) 1.48mol) to the compound of embodiment 134 preparations in batches 3(984.6g 7.38mol), makes temperature of charge keep below 10 ℃.Light brown suspension is stirred 10min, and (546mL, 7.38mol), drop rate should make temperature of charge remain on below 5 ℃ to drip EtSH then.After stirring 2.5h below 10 ℃, in the 6L frozen water under the slow impouring violent stirring of reaction mixture.Separate organic layer, (3 * 1L) extract water layer with methylene dichloride.(dried over sodium sulfate is used in 2 * 1L) washings to the dichloromethane layer water that merges then.Removal of solvent under reduced pressure obtains brown oil, and it is filtered (with 0-10%EtOAc/ hexane wash-out) by silicagel pad.Collect each several part, after removing the also vacuum-drying of desolvating, obtain yellow viscous oil shape title compound (314g, 96%). 1H NMR(CDCl 3)δ6.92(d，1H)，6.62(d，1H)，6.55(dd，1H)，4.10(q，2H)，3.43(q，1H)，2.75(m，2H)，2.64(dd，1H)，2.31(dd，1H)，2.29(m，1H)，1.67(m，1H)，1.20(t，3H)。MS(Cl)m/z 221[M+H] +。
Embodiment 136
Preparation 2-((1S)-5-{2-[5-methyl-2-(4-aminomethyl phenyl) (1,3-oxazole-4-yl)] oxyethyl group } indane Base) ethyl acetate
Figure C0281867601431
Under room temperature, argon atmospher, with embodiment 135 preparation [(1S)-5-hydroxyl-2,3-dihydro-1H-indenes-1-yl] ethyl acetate (507.5mg, 2.30mmol), the 2-[5-methyl-2-(4-aminomethyl phenyl)-1 of embodiment 10 preparation, 3-oxazole-4-yl] ethanol (500mg, 2.30mmol), TMAD (792.6mg, 4.60mmol) and Ph 3(1.21g, the anhydrous DCM suspension of 15mL 4.60mmol) stirs 12h to P.DCM is removed in decompression.Handle resistates with flash chromatography on silica gel method (1% acetonitrile/methylene dichloride) and obtain 2-((1S)-5-{2-[5-methyl-2-(4-aminomethyl phenyl) (1,3-oxazole-4-yl)] oxyethyl group } indanyl) ethyl acetate (776.3mg, 1.85mmol, 80.5%).HPLC/MS(M+H) +m/z 420.5。
Embodiment 137
Preparation 2-((1S)-5-{2-[5-methyl-2-(4-aminomethyl phenyl) (1,3-oxazole-4-yl)] oxyethyl group } indane Base) acetate
Figure C0281867601441
At room temperature, with 2-((1S)-5-{2-[5-methyl-2-(4-aminomethyl phenyl) (1,3-oxazole-4-yl)] oxyethyl group } indanyl) (embodiment 136 for ethyl acetate, 776.3mg, 1.85mmol) THF (4.0ml) solution add the LiOH aqueous solution (2M, 3.7ml, 7.4mmol), the mixture of water (2.0ml) and EtOH (4.0ml).It is muddy that the gained mixture becomes.Mixture is heated at 40 ℃ (oil bath temperatures).Finish at the 1.5h afterreaction.After being cooled to room temperature, 1N HCl solution is slowly added mixture until pH 4.0.(3 * 20ml) extract compound with EtOAc.The EtOAc layer dried over sodium sulfate that merges, evaporation then.Handle resistates with flash chromatography and obtain white solid 2-((1S)-5-{2-[5-methyl-2-(4-aminomethyl phenyl) (1,3-oxazole-4-yl)] oxyethyl group } indanyl) acetate (616.8mg, 1.57mmol, 85%). 1H NMR(CDCl 3)δ7.83(d，2H)，7.21(d，2H)，7.03(d，1H)，6.74(d，1H)，6.69(dd，1H)，4.19(t，2H)，3.45(q，1H)，2.93(t，2H)，2.78(m，2H)，2.51(m，2H)，2.30(s，3H)，2.25(s，3H)，1.53(m，2H)。
According to the method for the foregoing description 129-137 and use the suitable initial feed of alternate, prepare the formula Ia compound of following table 4 similarly.
Table 4
The preparation embodiment of formula (Ia) compound
Figure C0281867601442
Figure C0281867601451
Ex.No. R 3 R 4 LC/MS[M+H]
159 n-Pr Ph 406.5
160 Me 4-Ph-Ph 454.5
161 Me 3-Cl-Ph 412.4
162 Me 3-Me-Ph 392.5
163 Me 4-CN-Ph 403.4
164 Me 3-CN-Ph 403.4
165 Me 4-Cl-Ph 412.4
166 Me 3-CF3-Ph 446.4
167 Et 4-Et-Ph 420.5
168 Et 4-Me-Ph 406.5
169 Et 4-MeO-Ph 422.4
Embodiment 170
Preparation 4-bromo-3-oxopentanoic acid methyl esters
Figure C0281867601461
Under argon atmospher, the propionyl methyl acetate of packing in the dry three-necked flask (20g, trichloromethane 154mmol) (100mL) solution.0 ℃ with addition funnel in 2h dripping bromine (7.9mL, 24.6g, 154mmol).Allow reactant slowly rise to room temperature, stirred reaction mixture spends the night.Slowly add saturated sodium carbonate solution (40mL), behind the restir reaction mixture 15min, isolate each solvent layer, water layer extracts with methylene dichloride (50mL).The organic layer dried over sodium sulfate that merges is filtered, then concentrating under reduced pressure.Resistates is purified by the flash chromatography on silica gel method, and (10: 1 hexanes/EtOAc) obtain required light yellow oily bromide (25g, 78%). 1H NMR(CDCl 3)：δ1.80(d，3H)，3.64-3.92(m，2H)，3.78(s，3H)，4.61(q，1H)。
Embodiment 171
Preparation (2-amino-5-methyl isophthalic acid, 3-thiazole-4-yl) methyl acetate
Figure C0281867601471
Embodiment 170 bromides (18g, add in toluene 86mmol) (100mL) solution thiocarbamide (10.5g, 138mmol).Reaction mixture is heated to 100 ℃ of 1h, is cooled to room temperature, removal of solvent under reduced pressure.Resistates is dissolved in methylene dichloride (100mL), adds saturated solution of sodium bicarbonate (75mL), with mixture vigorous stirring 10min.Separate organic layer, dry (Na 2SO 4), filter, then concentrating under reduced pressure.Resistates obtains white solid product (10g, 63%) with the dichloromethane/hexane recrystallization.(C 7H 10N 2O 2S): LC-MS, RT 0.76min, M+H 187.0; 1H NMR (CDCl 3): δ 2.23 (s, 3H), 3.70 (s, 2H), 3.75 (s, 3H), 4.83-4.95 (broad peak s, 2H).
Embodiment 172
Preparation (2-bromo-5-methyl isophthalic acid, 3-thiazole-4-yl) methyl acetate
Figure C0281867601472
At-20 ℃, CuBr 2(4.03g, 18.1mmol) and nitrite tert-butyl (2.82mL, add in MeCN 23.8mmol) (210mL) solution embodiment 170 compound (2.95g, 15.9mmol).Reaction mixture slowly rises to 15 ℃, discharges to nitrogen in this temperature observation.Behind 15 ℃ of restir 2h, reaction mixture is with ether (400mL) dilution, with 10%HCl solution (200mL) washing.Isolate each solvent layer, water layer is used ether (2 * 300mL) extractions, dry (MgSO again 4) organic layer that merges, filter, then concentrating under reduced pressure.Resistates is purified by the flash chromatography on silica gel method, and (98: 2, hexane/EtOAc) obtained embodiment 172 bromides (1.6g, 40%) of colorless oil, solidifies when leaving standstill.(C 7H 8BrNO 2S)：LC-MS，RT 2.56min，M+H 250.3； 1H NMR(CDCl 3)：δ2.26(s，3H)，3.60(s，2H)，3.61(s，3H)。
Embodiment 173
Preparation 2-(2-bromo-5-methyl isophthalic acid, 3-thiazole-4-yl) ethanol
At-78 ℃, (3.80g adds DIBAL-H (33.4mL, 33.4mmol1.0M toluene solution) to the ester of embodiment 172 preparations in methylene dichloride 15.2mmol) (100mL) solution.Behind the 15min, solution is risen to 0 ℃, restir 90min.Drip the excessive DIBAL-H of the 2N HCl aqueous solution (50mL) quencher then.Isolate each solvent layer, (2 * 200mL) extract water layer with methylene dichloride.The organic layer that dry (sal epsom) merges filters, then concentrating under reduced pressure.Resistates is purified by the flash chromatography on silica gel method, and (5: 2 hexanes/EtOAc) obtain little yellow oil product (2.5g, 74%) leave standstill curing.(C 6H 8BrNOS) LC-MS, RT 1.38min, M+H 221.0; 1H NMR (CDCl 3): δ 2.31 (s, 3H), 2.82 (t, 2H), 2.90-3.00 (broad peak s, 1H), 3.89 (t, 2H).
Embodiment 174
Preparation (1S)-and 5-[2-(2-bromo-5-methyl isophthalic acid, 3-thiazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1- Base } ethyl acetate
Figure C0281867601482
Step 1.Embodiment 173 (975mg, 4.39mmol) and [(1S)-5-hydroxyl-2,3-dihydro-1H-indenes-1-yl] (1.06g adds Ph in THF 4.83mmol) (20mL) solution to ethyl acetate 3P (1.88g, 7.46mmol) and ADDP (1.96g, 7.46mmol).Vigorous stirring mixture 72h at room temperature, removal of solvent under reduced pressure, resistates is purified by the flash chromatography on silica gel method, and (6: 1 hexanes/EtOAc) obtain colorless oil product (1.4g, 76%) leave standstill curing.(C 19H 22BrNO 3S)LC-MS，RT 3.92min，M+H 424.5； 1H NMR(CDCl 3)：δ1.26(t，3H)，1.65-1.81(m，1H)，2.28-2.45(m，2H)，2.37(s，3H)，2.69(dd，1H)，2.75-2.93(m，2H)，3.07(t，2H)，3.44-3.56(m，1H)，4.15(t，2H)，4.18(q，2H)，6.67(dd，1H)，6.73(d，1H)，7.03(d，1H)。
Preparation ((1S)-5-{2-[5-(4-isopropyl phenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3- Dihydro-1H-indenes-1-yl) ethyl acetate
Step 2.Toluene (15mL) and 1, add in the mixture of 4-diox (3mL) step 1 compound (300mg, 0.708mmol), 4-isopropyl benzene boric acid (464mg, 2.83mmol) and PdCl 2(dppf). and methylene dichloride (52mg, 0.071mmol).Argon gas stream is by mixture 30min, and (3.7mL 7.08mmol), is heated to 75 ℃ of 18h with reactant to add the 2N sodium carbonate solution then.Then reaction mixture is cooled to room temperature, with EtOAc (200mL) dilution, with saturated sodium bicarbonate solution (50mL) washing.Dry (Na 2SO 4) organic layer, filter, then concentrating under reduced pressure.Resistates is purified by the flash chromatography on silica gel method, and (8: 1 hexanes/EtOAc) obtain colorless oil product (305mg, 93%).(C 28H 33NO 3S): LC-MS, RT 5.17min, M+H 464.5; 1H NMR (CDCl 3): δ 1.17-1.31 (m, 3H), 1.26 (s, 3H), 1.27 (s, 3H), 1.65-1.82 (m, 1H), 2.30-2.43 (m, 2H), 2.46 (s, 3H), 2.72 (dd, 1H), 2.78-3.00 (m, 3H), 3.17 (t, 2H), 3.46-3.57 (m, 1H), 4.17 (q, 2H), 4.27 (t, 2H), 6.71 (d, 1H), 6.78 (s, 1H), 7.04 (d, 1H), 7.55 (the AB quartet, 4H).
Embodiment 175
Preparation ((1S)-5-{2-[2-(4-isopropyl phenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3- Dihydro-1H-indenes-1-yl) acetate
Figure C0281867601492
To embodiment 174 (305mg, 0.657mmol) the solution of THF (8mL), water (8mL) and EtOH (4mL) mixture add LiOH (63mg, 2.63mmol).Vigorous stirring reaction mixture 24h, water (20mL) dilution is with ether (10mL) washing.Then with 1NHCl with aqueous phase as acidified to pH～1, with methylene dichloride (4 * 50mL) extraction.The organic layer that dry (sodium sulfate) merges filters, then concentrating under reduced pressure.Resistates is purified by the flash chromatography on silica gel method, and (95: 5 methylene dichloride/MeOH) obtain white solid product (189mg, 66%).(C 26H 29NO 3S): LC-MS, RT 3.95min, M+H 436.4; 1H NMR (CDCl 3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (the AB quartet, 4H).
Embodiment 176
Preparation { 5-methyl-2-(4-aminomethyl phenyl)-1,3-thiazoles-4-yl } methyl acetate
The bromide of embodiment 170 (1.15g, and adding 4-methyl thiobenzamide in toluene 5.52mmol) (20mL) solution (1.0g, 6.6mmol).Reaction mixture is heated to backflow 15h, is cooled to room temperature,, use saturated sodium bicarbonate solution (50mL) successively, saturated ammonium chloride solution (50mL) washing with EtOAc (150mL) dilution.Dry (sodium sulfate) organic layer filters, then concentrating under reduced pressure.Resistates is purified by the flash chromatography on silica gel method, and (9: 1 hexanes/EtOAc) obtain pinkish oily product leave standstill curing (1.14g, 62%). 1H NMR (CDCl 3): δ 2.38 (s, 3H), 3.45 (s, 3H), 3.74 (s, 3H), 3.80 (s, 2H), 7.49 (the AB quartet, 4H); R f(0.4,9: 1 hexanes of elutriant/EtOAc).
Embodiment 177
Preparation 2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-thiazoles-4-yl] ethanol
Figure C0281867601502
At 0 ℃, (1.14g, THF 4.37mmol) (60mL) solution adds LiAlH in batches to the thiazole of embodiment 176 4(663mg, 17.5mmol).Behind 30min, reaction mixture is risen to room temperature, restir 60min.Reaction mixture to 0 ℃ drips water (5mL), 1N NaOH (10mL) and the excessive LiAlH of water (5mL) quencher successively then 4Mixture is with the dilution of Rochelle salt saturated solution, with EtOAc (4 * 75mL) extractions.The organic phase dried over sodium sulfate that merges is filtered, then concentrating under reduced pressure.Resistates is purified by the flash chromatography on silica gel method, and (3: 2 hexanes/EtOAc) obtain white solid product (830mg, 82%).(C 13H 15NOS): LC-MS, RT 2.50min, M+H 234.2; 1H NMR (CDCl 3): δ 2.34 (s, 3H), 2.37 (s, 3H), 2.83 (t, 2H), 3.92-4.01 (broad peak t, 2H), 4.04-4.15 (broad peak s, 1H), 7.45 (the AB quartet, 4H).
According to the synthetic following compound of one of two kinds of methods of the foregoing description 170-177.
Embodiment 178
(1S)-and 5-[2-(5-methyl-2-phenyl-1,3-thiazoles-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } Acetate
Figure C0281867601511
(C 23H 23NO 3S)：LC-MS RT 3.56min，M+H 394.2； 1H NMR(CDCl 3)：δ1.61-1.78(m，1H)，2.19-2.50(m，2H)，2.30(s，3H)，2.62-2.91(m，3H)，3.12(t，2H)，3.17-3.26(m，1H)，4.12(t，2H)，6.70(d，1H)，6.79(s，1H)，6.98(d，1H)，7.21-7.40(m，3H)，7.74-7.83(m，2H)。
Embodiment 179
((1S)-5-{2-[5-methyl-2-(4-aminomethyl phenyl)-1,3-thiazoles-4-yl] oxyethyl group }-2,3-dihydro-1H- Indenes-1-yl) acetate
Figure C0281867601512
(C 24H 25NO 3S): LC-MS, RT 3.57min, M+H 408.5; 1H NMR (CDCl 3): δ 1.61-1.68 (m, 1H), 2.29 (s, 3H), 2.36 (s, 3H), 2.25-2.37[hides] (m, 2H), 2.63-2.79 (m, 3H), 3.09 (t, 2H), 3.35-3.47 (m, 1H), 4.18 (t, 2H), 6.60 (dd, 1H), 6.68 (s, 1H), 6.97 (d, 1H), 7.42 (the AB quartet, 4H), 7.81-8.30 (br, 1H).
Embodiment 180
((1S)-5-{2-[2-(1,3-Ben Bing Er Evil is luxuriant-the 5-yl)-the 5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3- Dihydro-1H-indenes-1-yl) acetate
Figure C0281867601521
(C 24H 23NO 5S)：LC-MS，RT 4.04min，M+H 438.5； 1H NMR(CDCl 3)：δ1.71-1.83(m，1H)，2.36-2.51(m，2H)，2.45(s，3H)，2.76-2.96(m，3H)，3.15(t，2H)，3.48-3.58(m，1H)，4.29(t，2H)，6.00(s，2H)，6.72(dd，1H)，6.78(s，1H)，6.82(d，1H)，7.07(d，1H)，7.32-7.40(m，2H)。
Embodiment 181
((1S)-5-{2-[2-(4-p-methoxy-phenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro- 1H-indenes-1-yl) acetate
Figure C0281867601522
(C 24H 25NO 4S): LC-MS, RT 4.01min, M+H 424.5; 1H NMR (CDCl 3): δ 1.67-1.82 (m, 1H), 2.43 (s, 3H), 2.34-2.47 (m, 2H), 2.72-2.95 (m, 3H), 3.09 (t, 2H), 3.42-3.57 (m, 1H), 3.84 (s, 3H), 4.13 (t, 2H), 6.72 (d, 1H), 6.79 (s, 1H), 7.12 (d, 1H), 7.37 (the AB quartet, 4H).
Embodiment 182
[(1S)-5-(2-{5-methyl-2-[4-(trifluoromethyl) phenyl]-1,3-thiazoles-4-yl } oxyethyl group)-2,3-two Hydrogen-1H-indenes-1-yl] acetate
(C 24H 22F 3NO 3S): LC-MS, RT 4.47min, M+H 462.4; 1H NMR (DMSO-d 6): δ 1.63-1.81 (m, 1H), 2.28-2.43 (m, 2H), 2.50 (s, 3H), 2.69 (dd, 1H), 2.74-2.95 (m, 2H), 3.19 (t, 2H), 3.31-3.36 (m, 1H), 4.31 (t, 2H), 6.71 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.87 (the AB quartet, 4H).
Embodiment 183
((1S)-5-{2-[2-(4-cyano-phenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3-dihydro-1H- Indenes-1-yl) acetate
Figure C0281867601532
(C 24H 22N 2O 3S): LC-MS, RT 3.43min, M+H 419.6; 1H NMR (CDCl 3): δ 1.68-1.85 (m, 1H), 2.31-2.49 (m, 2H), 2.51 (s, 3H), 2.77 (dd, 1H), 2.83-2.94 (m, 2H), 3.18 (t, 2H), 3.43-3.56 (m, 1H), 4.31 (t, 2H), 6.71 (dd, 1H), 6.79 (s, 1H), 7.10 (d, 1H), 7.86 (the AB quartet, 4H).
Embodiment 184
((1S)-5-{2-[2-(4-isopropyl phenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro- 1H-indenes-1-yl) acetate
Figure C0281867601533
(C 26H 29NO 3S): LC-MS, RT 3.95min, M+H 436.4; 1H NMR (CDCl 3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (the AB quartet, 4H).
Embodiment 185
((1S)-5-{2-[2-(3-chloro-4-fluorophenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro- 1H-indenes-1-yl) acetate
Figure C0281867601541
(C 23H 21ClFNO 3S)：LC-MS，RT 3.89min，M+H 446.4； 1H NMR(CDCl 3)：δ1.68-1.86(m，1H)，2.32-2.46(m，2H)，2.50(s，3H)，2.80(dd，1H)，2.84-2.96(m，2H)，3.18(t，2H)，3.47-3.59(m，1H)，4.32(t，2H)，6.72(d，1H)，6.82(s，1H)，7.12(d，1H)，7.23(t，1H)，7.72-7.82(m，1H)，7.97-8.04(m，1H)。
Embodiment 186
((1S)-5-{2-[2-(3, the 4-dichlorophenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro- 1H-indenes-1-yl) acetate
Figure C0281867601542
(C 23H 21Cl 2NO 3S)：LC-MS，RT 4.12min，M+H 462.0； 1H NMR(CDCl 3)：δ1.74-1.88(m，1H)，2.36-2.48(m，2H)，2.50(s，3H)，2.73-2.93(m，3H)，3.19(t，2H)，3.48-3.55(m，1H)，4.30(t，2H)，6.71(d，1H)，6.79(s，1H)，7.09(d，1H)，7.52(d，1H)，7.61(dd，1H)，8.02(d，1H)。
Embodiment 187
((1S)-5-{2-[2-(4-fluorophenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3-dihydro-1H-indenes -1-yl) acetate
Figure C0281867601551
(C 23H 22FNO 3S)：LC-MS，RT 3.58min，M+H 412.4； 1H NMR(CDCl 3)：δ1.70-1.77(m，1H)，2.37-2.45(m，1H)，2.44(s，3H)，2.70-2.90(m，4H)，3.16(t，2H)，3.47-3.52(m，1H)，4.27(t，2H)，6.70(d，1H)，6.76(s，1H)，7.00-7.10(m，3H)，7.82-7.87(m，2H)。
Embodiment 188
((1S)-5-{2-[2-(3, the 4-3,5-dimethylphenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro -1H-indenes-1-yl) acetate
Figure C0281867601552
(C 25H 27NO 3S): LC-MS, RT 4.39min, M+H 422.3; 1H NMR (CDCl 3): δ 1.70-1.83 (m, 1H), 2.29 (s, 3H), 2.32 (s, 3H), 2.37-2.50[hides] (m, 2H), 2.46 (s, 3H), 2.70.-2.90 (m, 3H), 3.32 (t, 2H), 3.45-3.60 (m, 1H), 4.30 (t, 2H), 6.73 (d, 1H), 6.79 (s, 1H), 7.07 (d, 1H), 7.17 (d, 1H), 7.59 (d, 1H), 7.68 (s, 1H).
Embodiment 189
((1S)-5-{2-[2-(4-acetylphenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro- 1-H-indenes-1-yl) acetate
Figure C0281867601553
(C 25H 25NO 4S)：LC-MS，RT 4.01min，M+H 436.3； 1H NMR(CDCl 3)：δ1.70-1.82(m，1H)，2.37-2.49(m，2H)，2.50(s，3H)，2.63(s，3H)，2.70-2.90(m，3H)，3.20(t，2H)，3.45-3.60(m，1H)，4.30(t，2H)，6.72(d，1H)，6.78(s，1H)，7.08(d，1H)，7.95-8.03(m，4H)。
Embodiment 190
[(1S)-5-(2-{2-[4-(dimethylamino) phenyl]-the 5-methyl isophthalic acid, 3-thiazole-4-yl } oxyethyl group)-2,3- Dihydro-1H-indenes-1-yl] acetate
Figure C0281867601561
(C 25H 28N 2O 3S): LC-MS, RT 2.95min, M+H 437.2; 1H NMR (DMSO D6): δ 1.53-1.65 (m, 1H), 2.12-2.24 (m, 2H), 2.36 (s, 3H), 2.63-2.84 (m, 3H), 2.94 (s, 6H), 3.03 (t, 2H), 3.27-3.38 (m, 1H), 4.18 (t, 2H), 6.65 (d, 1H), 6.75 (s, 1H), 7.08 (d, 1H), 7.17 (the AB quartet, 4H).
Embodiment 191
((1S)-5-{2-[2-(3-amino-4-aminomethyl phenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3- Dihydro-1H-indenes-1-yl) acetate
Figure C0281867601562
C 24H 26N 2O 3S.C 2F 3O 2)：LC-MS，RT 3.5min，M+H 423.3； 1H NMR(CD 3OD)：δ1.67-1.82(m，1H)，2.25-2.37(m，2H)，2.38(s，3H)，2.50(s，3H)，2.67-2.90(m，3H)，3.20(t，2H)，3.41-3.56(m，1H)，4.32(t，2H)，6.71(d，1H)，6.79(s，1H)，7.09(d，1H)，7.42(d，1H)，7.69(dd，1H)，7.77(d，1H)。
Embodiment 192
((1S) 5-{2-[2-(2-fluorophenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3-dihydro-1H-indenes -1-yl) acetate
(C 23H 22FNO 3S)：LC-MS，RT 4.25min，M+H 412.2； 1H NMR(CDCl 3)：δ1.70-1.82(m，1H)，2.37-2.48(m，2H)，2.49(s，3H)，2.74-2.94(m，3H)，3.21(t，2H)，3.42-3.60(m，1H)，4.31(t，2H)，6.72(d，1H)，6.79(s，1H)，7.06-7.35(m，4H)，8.21(t，1H)。
Embodiment 193
((1S)-5-{2-[2-(4-chloro-phenyl-)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3-dihydro-1H-indenes -1-yl) acetate
Figure C0281867601572
(C 23H 22ClNO 3S)：LC-MS，RT 4.44min，M+H 428.2； 1H NMR(CDCl 3)：δ1.70-1.81(m，1H)，2.35-2.45(m，2H)，2.46(s，3H)，2.74-2.89(m，3H)，3.17(t，2H)，3.42-3.60(m，1H)，4.28(t，2H)，6.71(d，1H)，6.77(s，1H)，7.07(d，1H)，7.36(d，2H)，7.79(d，2H)。
Embodiment 194
((1S)-5-{2-[2-(4-ethoxyl phenenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro- 1H-indenes-1-yl) acetate
Figure C0281867601573
(C 25H 27NO 4S)：LC-MS，RT 3.55min，M+H 438.5； 1H NMR(CDCl 3)：δ1.40(t，3H)，1.70-1.82(m，1H)，2.35-2.47(m，2H)，2.45(s，3H)，2.74-2.89(m，3H)，3.20(t，2H)，3.42-3.59(m，1H)，4.07(q，2H)，4.29(t，2H)，6.71(d，1H)，6.76(s，1H)，6.91(d，1H)，7.06(d，2H)，7.82(d，2H)。
Embodiment 195
((1S)-5-{2-[2-(3, the 4-Dimethoxyphenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3-two Hydrogen-1H-indenes-1-yl) acetate
Figure C0281867601581
(C 25H 27NO 5S): LC-MS, RT 3.86min, M+H 454.2; 1H NMR (CDCl 3): δ 1.67-1.82 (m, 1H), 2.37-2.48 (m, 2H), 2.49 (s, 3H), 2.71-2.87 (m, 3H), 3.27 (t, 2H), 3.42-3.57 (m, 1H), 3.93 (s, 3H), 3.96 (s, 3H), 4.29 (t, 2H), 6.35-6.64 (broad peak s, 1H), 6.67 (d, 1H), 6.75 (s, 1H), 6.89 (d, 1H), 7.05 (d, 1H), 7.39 (d, 1H), 7.56 (s, 1H).
Embodiment 196
((1S)-5-{2-[5-methyl-2-(3-aminomethyl phenyl)-1,3-thiazoles-4-yl] oxyethyl group }-2,3-dihydro-1- Indenes-1-yl) acetate
(C 24H 25NO 3S)：LC-MS，RT 3.71min，M+H 408.2； 1H NMR(CDCl 3)：δ1.70-1.82(m，1H)，2.38-2.52(m，2H)，2.40(s，3H)，2.47(s，3H)，2.75-2.87(m，3H)，3.19(t，2H)，3.45-3.60(m，1H)，4.29(t，2H)，6.72(d，1H)，6.78(s，1H)，7.07(d，1H)，7.19(d，1H)，7.30(t，1H)，7.64(d，1H)，7.75(s，1H)。
Embodiment 197
[(1S)-5-(2-{5-methyl-2-[3-(trifluoromethyl) phenyl]-1,3-thiazoles-4-yl } oxyethyl group)-2,3-two Hydrogen-1H-indenes-1-yl] acetate
(C 24H 22F 3NO 3S)：LC-MS，RT 3.90min，M+H 462.1； 1H NMR(CDCl 3)：δ1.70-1.82(m，1H)，2.38-2.48(m，2H)，2.49(s，3H)，2.75-2.87(m，3H)，3.19(t，2H)，3.44-3.59(m，1H)，4.30(t，2H)，6.72(d，1H)，6.79(s，1H)，7.07(d，1H)，7.52(t，1H)，7.61(d，1H)，8.01(d，1H)，8.13(s，1H)。
Embodiment 198
((1S)-5-{2-[2-(3-fluorophenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3-dihydro-1H-indenes -1-yl) acetate
Figure C0281867601592
(C 23H 22FNO 3S)：LC-MS，RT 3.66min，M+H 412.1； 1H NMR(CDCl 3)：δ1.70-1.82(m，1H)，2.39-2.47(m，2H)，2.48(s，3H)，2.76-2.87(m，3H)，3.18(t，2H)，3.45-3.60(m，1H)，4.30(t，2H)，6.72(d，1H)，6.78(s，1H)，7.04-7.09(m，2H)，7.36-7.42(m，1H)，7.58-7.62(m，2H)。
Embodiment 199
((1S)-5-{2-[2-(3, the 5-3,5-dimethylphenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro -1H-indenes-1-yl) acetate
Figure C0281867601601
(C 25H 27NO 3S)：LC-MS，RT 3.88min，M+H 422.2； 1H NMR(CDCl 3)：δ1.72-1.84(m，1H)，2.36(s，6H)，2.37-2.45(m，2H)，2.46(s，3H)，2.75-2.87(m，3H)，3.19(t，2H)，3.45-3.60(m，1H)，4.28(t，2H)，6.72(d，1H)，6.79(s，1H)，7.01(s，1H)，7.07(d，1H)，7.48(s，2H)。
Embodiment 200
[(1S)-5-(2-{5-methyl-2-[4-(trifluoromethoxy) phenyl]-1,3-thiazoles-4-yl } oxyethyl group)-2,3- Dihydro-1H-indenes-1-yl] acetate
Figure C0281867601602
(C 24H 22F 3NO 4S)：LC-MS，RT 3.95min，M+H 478.1； 1H NMR(CDCl 3)：δ1.72-1.84(m，1H)，2.38-2.46(m，2H)，2.47(s，3H)，2.75-2.87(m，3H)，3.18(t，2H)，3.45-3.60(m，1H)，4.29(t，2H)，6.72(d，1H)，6.77(s，1H)，7.07(d，1H)，7.24(d，2H)，7.88(d，2H)。
Embodiment 201
((1S)-5-{2-[2-(3-p-methoxy-phenyl)-5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2, the 3-dihydro- 1H-indenes-1-yl) acetate
Figure C0281867601603
(C 24H 25NO 4S)：LC-MS，RT 3.56min，M+H 424.2； 1H NMR(CDCl 3)：δ1.70-1.82(m，1H)，2.37-2.52(m，2H)，2.49(s，3H)，2.75-2.87(m，3H)，3.19(t，2H)，3.45-3.57(m，1H)，3.87(s，3H)，4.30(t，2H)，6.72(d，1H)，6.79(s，1H)，6.95(d，1H)，7.10(d，1H)，7.32(t，1H)，7.40-7.45(m，2H)。
Embodiment 202
((1S)-5-{2-(1,1 '-xenyl-4-yl)-the 5-methyl isophthalic acid, 3-thiazole-4-yl] oxyethyl group }-2,3-two Hydrogen-1H-indenes-1-yl) acetate
(C 29H 27NO 3S)：LC-MS，RT 3.96min，M+H 470.3； 1H NMR(CDCl 3)：δ1.70-1.81(m，1H)，2.38-2.48(m，2H)，2.49(s，3H)，2.75-2.87(m，3H)，3.20(t，2H)，3.43-3.59(m，1H)，4.31(t，2H)，6.72(d，1H)，6.79(s，1H)，7.08(d，1H)，7.36(t，1H)，7.45(t，2H)，7.61-7.65(m，4H)，7.93(d，2H)。
Embodiment 203
Preparation (1S)-and 5-[2-(4-methyl-2-phenyl-1,3-oxazole-5-yl) oxyethyl group]-2,3-dihydro-1H-indenes- The 1-yl } ethyl acetate
Figure C0281867601612
(0.205g 0.81mmol) adds PPh with ADDP 3(0.212g, 0.81mmol), [(1S)-and 5-hydroxyl-2,3-dihydro-1H-indenes-1-yl] ethyl acetate (0.107g, 0.49mmol) and 2-(4-methyl-2-phenyl-1,3-oxazole-5-yl) (embodiment 51 steps 4,0.110g is 0.54mmol) at the mixture of THF (5mL) for ethanol.At room temperature reaction stirred is spent the night, again with ADDP (0.136g, 0.54mmol) and PPh 3(0.141g 0.54mmol) adds with methylene dichloride (5mL).At room temperature stirred solution 24h filters.Evaporated filtrate, the gained mixture is with Biotage purify (0-50%EtOAc/ hexane gradient).Obtain little yellow oily (1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazole-5-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } ethyl acetate (0.145g, 66% yield).ES-MS m/z 406.2 ((MH) +); HPLC RT (min) 3.89; 1H NMR (acetone-d 6) δ 7.85-7.82 (m, 2H), 7.36-7.30 (m, 3H), 6.94 (d, 1H), 6.65 (s, 1H), 6.60-6.55 (m, 1H), 4.10 (t, 2H), 3.98 (q, 2H), 3.31-3.27 (m, 1H), 3.03 (t, 2H), 3.27-2.51 (m, 3H), 2.24-2.14 (m, 2H), 2.18 (s, 3H), 1.58-1.53 (m, 1H), 1.08 (t, 3H).
Embodiment 204
Preparation (1S)-and 5-[2-(4-methyl-2-phenyl-1,3-oxazole-5-yl) oxyethyl group]-2,3-dihydro-1H-indenes- The 1-yl } acetate
Figure C0281867601621
Will (1S)-and 5-[2-(4-methyl-2-phenyl-1,3-oxazole-5-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } ethyl acetate (0.135g 0.33mmol) is dissolved in EtOH (6mL), and adding LiOH (0.024g, 1.0mmol).Add entry (3mL), add THF and become clarification until turbid solution.At room temperature stir the gained mixture overnight.Add HCl (2N) and regulate pH to 2, use ethyl acetate extraction then three times.Merge organic layer, drying, concentrated then acquisition colorless oil (1S)-and 5-[2-(4-methyl-2-phenyl-1,3-oxazole-5-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } acetate (0.039g, 30.6% yield).ES-MS m/z 378.2 ((MH) +); HPLC RT (min) 3.22; 1H NMR (acetone-d 6) δ 8.1 (s br 1H) 8.0-7.95 (m, 2H), 7.52-7.43 (m, 3H), 7.15 (d, 1H), 6.81 (s, 1H), 6.73 (d, 1H), 4.27 (t, 2H) 3.47-3.40 (m, 1H), 3.18 (t, 2H), 2.90-2.68 (m, 3H), and 2.41-2.29 (m, 2H), 2.18 (s, 3H), and 1.77-1.68 (m, 1H).
According to the method for the foregoing description 51,203 and 204 and use the suitable initial feed of alternate, prepare similarly and characterize following compound.
Embodiment 205
Preparation N-(4-methyl benzoyl) L-Ala
Figure C0281867601631
1H NMR(DMSO-d 6)δ12.60(s br，1H)，8.57(d，1H)，7.81(d，2H)，7.28(d，2H)，4.38(q，1H)，2.35(s，3H)，1.38(d，3H)。
Embodiment 206
Preparation N-(3-fluoro-4-methyl benzoyl) L-Ala
Figure C0281867601632
1H NMR(DMSO-d 6)δ12.54(sbr，1H)，8.67(d，1H)，7.65-7.62(m，2H)，7.39(t，1H)，4.38(q，1H)，2.27(s，3H)，1.38(d，3H)。
Embodiment 207
Preparation N-[4-(trifluoromethyl) benzoyl] L-Ala
Figure C0281867601633
1H NMR(DMSO-d 6)δ12.64(s br，1H)，8.91(d，1H)，8.08(d，2H)，7.85(d，2H)，4.42(q，1H)，1.40(d，3H)。
Embodiment 208
Preparation 4-[(4-methyl benzoyl) amino]-3-oxopentanoic acid ethyl ester
Figure C0281867601634
ES-MS m/z 278.38((MH) +)；HPLC RT(min)2.04。 1H NMR (acetone-d 6) δ 8.08 (s br, 1H), 7.90 (d, 2H), 7.28 (d, 2H), 4.72-4.67 (m, 1H), 4.13 (q, 2H), 3.66 (s, 2H), 2.40 (s, 3H), 1.41 (d, 3H), 1.12 (t, 3H).
Embodiment 209
Preparation 4-[(3-fluoro-4-methyl benzoyl) amino]-3-oxopentanoic acid ethyl ester
Figure C0281867601641
ES-MS m/z 296.4((MH) +)；HPLC RT(min)2.26。 1H NMR (acetone-d 6) δ 7.75-7.60 (m, 2H), 7.38 (t, 1H), 4.20 (q, 2H), 3.65 (s, 2H), 2.23 (s, 3H), 1.45 (d, 3H), 1.20 (t, 3H).
Embodiment 210
Preparation 3-oxo-4-{[4-(trifluoromethyl) benzoyl] amino } Valeric acid ethylester
Figure C0281867601642
ES-MS m/z 332.4((MH) +)；HPLC RT(min)2.45。 1H NMR (acetone-d 6) δ 8.14 (d, 2H), 7.84 (d, 2H), 4.80-4.74 (m, 2H), 4.20 (q, 2H), 3.70 (s, 2H), 1.48 (d, 3H), 1.21 (t, 3H).
Embodiment 211
Preparation [4-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-5-yl] ethyl acetate
Figure C0281867601643
ES-MS m/z 260.2((MH) +)；HPLC RT(min)2.96。 1H NMR (acetone-d 6) δ 7.86 (d, 2H), 7.30 (d, 2H), 4.15 (q, 2H), 3.81 (s, 2H), 2.37 (s, 3H), 2.14 (s, 3H), 1.24 (t, 3H).
Embodiment 212
Preparation [2-(3-fluoro-4-aminomethyl phenyl)-4-methyl isophthalic acid, 3-oxazole-5-yl] ethyl acetate
Figure C0281867601651
ES-MS m/z 278.3((MH) +)；HPLC RT(min)2.89。 1H NMR (acetone-d 6) δ 7.69 (d, 1H), 7.60 (d, 1H), 7.37 (t, 1H), 4.15 (q, 2H), 3.83 (s, 2H), 2.31 (s, 3H), 2.15 (s, 3H), 1.23 (t, 3H).
Embodiment 213
Preparation 4-methyl-2-[4-(trifluoromethyl) phenyl] and-1,3-oxazole-5-yl } ethyl acetate
Figure C0281867601652
ES-MS m/z 314.3((MH) +)；HPLC RT(min)3.27。 1H NMR (acetone-d 6) δ 8.18 (d, 2H), 7.84 (d, 2H), 4.17 (q, 2H), 3.88 (s, 2H), 2.20 (s, 3H), 1.23 (t, 3H).
Embodiment 214
Preparation 2-[4-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-5-yl] ethanol
Figure C0281867601653
ES-MS m/z 218.2((MH) +)；HPLC RT(min)2.35。 1H NMR (acetone d 6) δ 7.85 (d, 2H), 7.27 (d, 2H), 3.99 (s br, 1H), 3.83 (t, 2H), 2.90 (t, 2H), 2.37 (s, 3H), 2.12 (s, 3H).
Embodiment 215
Preparation 2-[2-(3-fluoro-4-aminomethyl phenyl)-4-methyl isophthalic acid, 3-oxazole-5-yl] ethanol
Figure C0281867601661
ES-MS m/z 236.2((MH) +)；HPLC RT(min)2.46。 1H NMR(CDCl 3)δ7.54(d，1H)，7.43(d，1H)，7.17(t，1H)，3.91(d，2H)，3.09(s br，1H)，2.88(t，2H)，2.29(s，3H)，2.13(s，3H)。
Embodiment 216
Preparation 2-{4-methyl-2-[4-(trifluoromethyl) phenyl]-1,3-oxazole-5-yl } ethanol
Figure C0281867601662
ES-MS m/z 272.2((MH) +)；HPLC RT(min)2.71。 1H NMR(CDCl 3)δ8.03(2，2H)，7.66(d，2H)，3.95(t，2H)，2.96(t，2H)，2.21(s，3H)，1.97(s br，1H)。
Embodiment 217
Preparation [(1S)-5-(2-{4-methyl-2-[4-(trifluoromethyl) phenyl]-1,3-oxazole-5-yl } oxyethyl group)- 2,3-dihydro-1H-indenes-1-yl] ethyl acetate
Figure C0281867601663
ES-MS m/z 474.5((MH +)；HPLC RT(min)4.10。 1H NMR (acetone-d 6) 8.16 (d, 2H), 7.83 (d, 2H), 7.09 (d, 1H), 6.80 (s, 1H), 6.72 (dd, 1H), 4.28 (t, 2H), 4.12 (q, 2H), 3.46-3.41 (m, 1H), 3.21 (t, 2H), 2.86-2.65 (m, 3H), 2.39-2.26 (m, 2H), 2.20 (s, 3H), 1.75-1.63 (m, 1H), 1.22 (t, 3H).
Embodiment 218
Preparation ((1S)-5-{2-[4-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-5-yl] oxyethyl group }-2,3-two Hydrogen-1H-indenes-1-yl) ethyl acetate
Figure C0281867601671
TCL R f=0.22 hexane/EtOAc 4: 1
Embodiment 219
Preparation ((1S)-5-{2-[2-(3-fluoro-4-aminomethyl phenyl)-4-methyl isophthalic acid, 3-oxazole-5-yl] oxyethyl group }- 2,3-dihydro-1H-indenes-1-yl) ethyl acetate
Figure C0281867601672
ES-MS m/z 438.2((MH +)；HPLC RT(min)4.18。 1H NMR (acetone-d 6) δ 6.67 (dd, 1H), 7.59 (dd, 1H), 7.37 (t, 1H), 7.08 (d, 1H), 6.80 (s, 1H), 6.72 (dd, 1H), 4.26 (t, 2H), 4.12 (q, 2H), 3.46-3.38 (m, 1H), 3.17 (t, 2H), 2.89-2.65 (m, 3H), 2.39-2.23 (m, 5H), 2.17 (s, 3H), 1.75-1.63 (m, 1H), 1.23 (t, 3H).
Embodiment 220
Preparation ((1S)-5-{2-[4-methyl-2-(4-aminomethyl phenyl)-1,3-oxazole-5-yl] oxyethyl group }-2,3-two Hydrogen-1H-indenes-1-yl) acetate
Figure C0281867601681
ES-MS m/z 392.2 ((MH) +); HPLC RT (min) 3.36. 1H NMR (acetone-d 6) δ 7.72 (d, 2H), 7.15 (d, 2H), 6.99 (d, 1H), 6.67 (s, 1H), 6.59 (dd, 1H), 4.12 (t, 2H), 3.33-3.28 (m, 1H), 3.03 (t, 2H), 2.73-2.54 (m, 3H), 2.27-2.21 (m, 5H), 2.02 (s, 3H), 1.64-1.54 (m, 1H).
Embodiment 221
Preparation ((1S)-5-{2-[2-(3-fluoro-4-aminomethyl phenyl)-4-methyl isophthalic acid, 3-oxazole-5-yl] oxyethyl group }- 2,3-dihydro-11-indenes-1-yl) acetate
Figure C0281867601682
ES-MS m/z 410.2((MH) +)；HPLC RT(min)3.49。 1H NMR (acetone-d 6) δ 7.68 (dd, 1H), 7.59 (dd, 1H), 7.36 (t, 1H), 7.12 (d, 1H), 6.80 (s, 1H), 6.72 (dd, 1H), 4.26 (t, 2H), 3.47-3.41 (m, 1H, 3.18 (t, 2H), 2.86-2.67 (m, 3H), 2.40-2.28 (m, 5H), 2.17 (s, 3H), 1.18-1.65 (m, 1H).
Embodiment 222
Preparation [(1S)-5-(2-{4-methyl-2-[4-(trifluoromethyl) phenyl]-1,3-oxazole-5-yl } oxyethyl group)- 2,3-dihydro-1H-indenes-1-yl] acetate
Figure C0281867601691
ES-MS m/z 446.5((MH) +)；HPLC RT(min)3.47。 1H NMR (acetone-d 6) δ 8.17 (d, 2H), 7.84 (d, 2H), 7.13 (s, 1H), 6.80 (s, 1H), 6.72 (dd, 1H), 4.28 (t, 2H), 3.46-3.41 (m, 1H), 3.21 (t, 2H), 2.86-2.67 (m, 3H), 2.40-2.28 (m, 2H), 2.20 (s, 3H), 1.77-1.67 (m, 1H).
Embodiment 223
Preparation (2S)-2-{ (1S)-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]-2,3 dihydros- 1H-indenes-1-yl } propionic acid and (2R)-2-{ (1R)-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) second The oxygen base)-2,3-dihydro-1H-indenes-1-yl } propionic acid
Figure C0281867601692
Step 1. preparation (2S)-2-[(1S)-5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] propionic acid and (2R)-2-[(1R)-and 5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] propionic acid
Figure C0281867601693
Under the 60psi nitrogen atmosphere, make initial acid (embodiment 2b) reaction according to the similar approach of embodiment 4 with the 45mL ethanol and the 5mL THF solution of 4.5g initial feed, 1.04g catalyzer and 4.5mL triethylamine.After the standard extraction treatment, obtain the 3.22g product.LC/MS retention time 2.41min, NMR (d6-DMSO): 0.87 (d, 3H, Alpha-Methyl), 1.75 (m, 1H), 2.04 (m, 1H), (3.66 s, 3H, methoxyl group), 6.65 (m, 1H, aryl), 6.76 (s, 1H, aryl), 7.04 (d, 1H, aryl) 12.18 (bs, 1H, acid).
Step 2: preparation (2S)-2-[(1S)-5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] the propionic acid first Ester and (2R)-2-[(1R)-5-methoxyl group-2,3-dihydro-1H-indenes-1-yl] methyl propionate
Under embodiment 6 described standard enzymatic synthesis conditions, with 1.5g initial acid, 0.93mL methyl iodide and 1.75g sodium bicarbonate above compound of prepared in reaction in 10mL methyl alcohol.Progressively handle and obtain 1.53g, 96%.(NMR (CD 2Cl 2): 1.05 (d, 3H, Alpha-Methyls), 1.88 (m, 1H), 2.19 (m, 1H), 3.44 (m, 1H), 3.68 (s, 3H, methoxyl groups), 3.77 (s, 3H, esters).
Step 3. preparation (2S)-2-[(1S)-5-hydroxyl-2,3-dihydro-1H-indenes-1-yl] methyl propionate (2R)-2-[(1R)-and 5-hydroxyl-2,3-dihydro-1H-indenes-1-yl] methyl propionate
Figure C0281867601702
Adopt demethylation condition (1.53g initial feed, the 4.35g AlCl of embodiment 7 320mL dichloromethane solution with the 2.4mL sulfur alcohol) obtains 1.21g product (84%).(NMR (CD 2Cl 2): 1.05 (d, 3H, Alpha-Methyls), 1.88 (m, 1H), 2.18 (m, 1H), 3.45 (m, 1H), 3.67 (s, 3H, esters), 6.60 (m, 1H, aryl), 6.69 (s, 1H, aryl), 6.93 (d, 1H, aryl).
Step 4: preparation (2S)-2-{ (1S)-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) second The oxygen base]-2,3-dihydro-1H-indenes-1-yl } methyl propionate and (2R)-2-{ (1R)-5-[2-(5-methyl-2-benzene Base-1,3-oxazole-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } methyl propionate
Figure C0281867601711
According to the standard Mitsunobu couling process (the 2mL dichloromethane solution of the initial phenol of 0.100g, 0.110g oxazolyl ethanol, 0.143g triphenylphosphine and 0.137g ADDP) that embodiment 11 introduces, handle the back in chromatography (15%EtOAc/ hexane) and obtain 0.107g (58%) product.(NMR (CD 2Cl 2): 1.62-1.87 (m, 4H), 2.40 (s, 3H ， oxazole methyl), 2.98 (t, 2H, methylene radical), 3.23 (m, 1H), 3.63 (s, 3H, esters), 6.60 (s, 1H, aryl), 6.64 (m, 1H, aryl), 7.42 (m, 3H, aryl), 8.00 (m, 2H, aryl).
Step 5:(2S)-2-{ (1S)-5-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl) oxyethyl group]- 2,3-dihydro-1H-indenes-1-yl } propionic acid and (2R)-2-{ (1R)-5-[2-(5-methyl-2-phenyl-1,3-Evil Azoles-4-yl) oxyethyl group]-2,3-dihydro-1H-indenes-1-yl } propionic acid
Figure C0281867601712
The LiOH hydrolysising condition is applied to the initial ester of 0.090g obtains 0.082g (95%) product.NMR (CD 3OD): 0.4-0.75 (m, 4H), 1.18 (s, 3H), 1.75 (t, 2H, methylene radical), 2.00 (m, 1H), (2.99 t, 2H, methylene radical), 5.39 (s, 1H, aryl), 5.48 (m, 1H, aryl), (5.83 d, 1H, aryl), 6.27 (m, 3H, aryl), 6.76 (m, 2H, aryl).
Use aforesaid method and suitable initial feed, prepare similarly other (2S, 1S) and (2R, 1R), both can for diastereomer (be cis (2S, 1S)/(2R, 1R) } and/or trans { (2S, 1S)/(2R, 1R) }) mixture, also can be independent enantiomer.These compounds are summarized in the table 5.
Table 5
Figure C0281867601721
Ex. No. R 3 R 4 X Isomer HPLC RT (min) LC-MS [M+H] +
224 Me 3，4-(Cl) 2-Ph O 2S，1S 4.10 460.0
225 Me 3，4-(Cl) 2-Ph O The cis racemic modification 4.10 460.0
226 Me 3，4-(Me) 2-Ph O The cis racemic modification 4.32 420.4
227 Me 3，4-(Me) 2-Ph O 2S，1S 4.32 420.4
228 Me 3-Me-Ph O The cis racemic modification 4.19 406.3
229 Me 4-CF 3-Ph O The cis racemic modification 3.73 460.2
230 Me 4-CF 3-Ph O 2S，1S 3.73 460.2
231 Me 4-CF 3-Ph O 2R，1R 3.73 460.2
232 Me 4-Cl-Ph O The cis racemic modification 3.61 426.2
233 Me 4-Et-Ph O The cis racemic modification 3.70 420.3
234 Me 4-Et-Ph O 2S，1S 3.70 420.3
235 Me 4-Et-Ph O 2R，1R 3.70 420.3
236 Me 4-Et-Ph O The cis/trans mixture 3.70 420.3
237 Me 4-Et-Ph O 2R，1S 3.70 420.3
238 Me 4-Et-Ph O 2S，1R 3.70 420.3
239 Me 4-MeO-Ph O The cis racemic modification 3.37 422.3
240 Me 4-MeO-Ph O 2R，1R 3.37 422.3
241 Me 4-MeO-Ph O 2S，1S 3.37 422.3
242 Me 4-n-Bu-Ph O The cis racemic modification 4.08 448.4
243 Me 4-t-Bu-Ph O 2S，1S 4.59 448.4
244 Et 4-t-Bu-Ph O The cis racemic modification 4.59 448.4
245 Me 4-MeO-Ph O 2S，1S 3.58 -
246 Me 4-Cl-Ph S The cis racemic modification 3.84 442.2
247 Me 4-Me-Ph S The cis racemic modification 4.34 422.3
Embodiment 248
Preparation [(1S)-5-(2-{2-[4 '-(5-ethanoyl-2-thienyl)-1,1 '-xenyl-4-yl]-the 5-methyl- 1,3-oxazole-4-yl } oxyethyl group)-2,3-dihydro-1H-indenes-1-yl] ethyl acetate
To comprising ((1S)-5-{2-[2-(4-bromophenyl)-5-methyl isophthalic acid; 3-oxazole-4-yl] oxyethyl group }-2; 3-dihydro-1H-indenes-1-yl) ethyl acetate (0.100g; 0.21mmol) [with 2-[5-methyl-2-(4-bromophenyl)-1; 3-oxazole-4-yl] ethanol and [(1S)-5-hydroxyl-2; 3-dihydro-1H-indenes-1-yl] ethyl acetate (embodiment 135) preparation]; 1; 1 '-two (diphenylphosphino)-ferrocene] palladium chloride (II) (16.9mg; 0.02mmol) and 5-ethanoyl-2-thienyl boric acid (0.062g; 0.41mmol) degassed toluene with diox (4: 1,2mL) add 2M aqueous sodium carbonate (0.5mL) in the solution.Mixture is heated 16h at 85 ℃.Vacuum evaporating solvent is dissolved in methyl alcohol and acetonitrile with resistates, filters by C8 reversed phase extraction post.Evaporating solvent is dissolved in acetonitrile with resistates, by HPLC purify to obtain [(1S)-5-(2-{2-[4 '-(5-ethanoyl-2-thienyl)-1; 1 '-xenyl-4-yl]-the 5-methyl isophthalic acid; 3-oxazole-4-yl } oxyethyl group)-2,3-dihydro-1H-indenes-1-yl] ethyl acetate, yield 46%.(50mg, 0.09mmol) MS (electron spray(ES)) 530.4 (M+H) +, 1H NMR (CDCl 3) δ 1.24 (t, 3H), 1.71 (m, 1H), 2.37 (m, 5H), 2.57 (s, 3H), 2.68 (m, 1H), 2.83 (m, 2H), 3.03 (m, 2H), 3.48 (m, 1H), 4.17 (m, 4H), 6.67 (m, 2H), 7.02 (d, 1H), 7.39 (d, 1H), 7.67 (d, 1H), 7.73 (d, 2H), 8.01 (d, 2H).
Other compounds are described in following table 6, prepare these compounds by the method parallel connection of using similar initial feed and embodiment 248 to introduce with the hydrolysis reaction that embodiment 11 introduces.
Table 6
Figure C0281867601741
Figure C0281867601742
The evaluation of compound
The compounds of this invention active with this area known external, in vitro with body in detection method confirm.For example, in order to confirm the curative effect of the following disease of a kind of pharmacological agent: for example X syndrome, glucose tolerance reduce for diabetes and relative disease, fasting plasma glucose raises and hyperinsulinemia; Perhaps for example hypertriglyceridemia and hypercholesterolemia of Atheromatosis and relative disease; Can use following detection method.
The insulin receptor combination of the 3T3-L1 cell of handling with all cpds
With 3T3-L1 with 9300 cell inoculations in every hole to the flat TC plate of Costar, cultivated for 1 week, after cytogamy 2 days (for example cell reaches maximum density).Handled cell 2 days with the division culture medium that contains 0.5 μ M human insulin-like growth factor (IGF-1) and test-compound (Eagle substratum (DMEM), 100 μ g/ml penicillin/streptomycin, 2mM L-glutaminate, 10% foetal calf serum of Dulbecco improvement) then.After the processing, change substratum, with cell cultures 4 days with division culture medium.Detect the insulin receptor activity of cell then.Behind the damping fluid washed cell, it is used 0.1nM 125I-Regular Insulin and (+/-) unmarked Regular Insulin incubation of 100nM, at room temperature incubation is 1 hour.Use the damping fluid washed cell afterwards 3 times,, count with gamma counter with the 1NNaOH dissolving.If reaching steady state determines the EC50 value and calculates maximal stimulation effect percentage.
Measure in the body
Detect the method for blood glucose concentration
(from Jackson Laboratories, Bar Harbor, Me acquisition) gets blood (from eye or tail vein) from the db/db mouse, according to average blood sugar concentration same packets.Mouse oral administration (with pharmaceutically acceptable solvent tube feed) gives test-compound every day once, continues 14 days.At this moment, get blood through eye or tail vein from mouse once more, measure blood sugar concentration.Under each situation, (Bayer Corporation, Elkhart IN) detect glucose concn with Glucometer Elite XL.
Detect the method for triglyceride concentration
(from Jackson Laboratories, Bar Harbor, Me acquisition) gets blood (from eye or tail vein) from the hApoA1 mouse, according to average serum triglyceride concentration same packets.Mouse oral administration (with pharmaceutically acceptable solvent tube feed) gives test-compound every day once, continues 8 days.And then get blood from mouse through eye or tail vein, measure serum triglyceride concentration.Under each situation, (Bayer Corporation, Tarrytoun NY) detect triglyceride concentration with Technicon Axon Autoandlyzer.
Detect the method for HDL-cholesterol concentration
In order to measure blood plasma HDL-cholesterol concentration, get blood from the hApoA1 mouse, according to average blood plasma HDL-cholesterol concentration same packets.Mouse orally give every day solvent or test-compound 1 time continuous 7 days, were got blood then again at the 8th day.Use Synchron ClinicalSystem (CX4) (Beckman Coulter, Fullerton, CA) analysed for plasma HDL-cholesterol.
Detect the method for total cholesterol, HDL-cholesterol, triglyceride level and glucose concn
In measuring in another kind of body, get blood from fat monkey, orally give solvent or test-compound once a day continued for 4 weeks then, got blood afterwards again.Use Synchron ClinicalSystem (CX4) (Beckman Coulter, Fullerton, CA) the total cholesterol in the serum analysis, HDL-cholesterol, triglyceride level and glucose.As (Proc.Natl.Acad.Sci.USA 98:5306-5311,2001) as described in the Oliver etc., use MR spectrum to carry out the analysis of lipoprotein subclass.
Detection is to the method for the influence of cardio-vascular parameters
Also estimated cardio-vascular parameters (for example heart rate and blood pressure).Orally give SHR rat solvent or test-compound once a day, continuous 2 weeks.Use and cut off tail method measurement blood pressure and heart rate, referring to (Am.J.Hypertens.13:370-375,2000) such as Grinsell.For monkey, as (J.Pharmacol.Exp.Therap.278:1435-1443,1996) monitoring blood pressure and heart rate as described in the Shen etc.
The compounds of this invention uses above-mentioned detection method test, by the living features that is obtained, find that The compounds of this invention has effect to blood sugar concentration and serum triglyceride concentration, therefore, for example X syndrome, glucose tolerance reduce, fasting plasma glucose raises and hyperinsulinemia to can be used for treating diabetes and relative disease; Perhaps for example hypertriglyceridemia and hypercholesterolemia of cardiovascular disorder and relative disease.
Medicinal compositions
According to above test or other result who is used to measure all perception methods and the comparison The above results of the curative effect for the treatment of the above-mentioned disease of Mammals and is used for the treatment of the known drug of above-mentioned illness, can determine at an easy rate that The compounds of this invention is used for the treatment of every kind of indication effective dose.Described activeconstituents is used for the treatment of different factors that a kind of dosage of above-mentioned illness considers as required and obviously different, for example the dosage forms unit of particular compound and use, application method, treatment time, the patient's age for the treatment of and sex, sanatory nature and extent.
The activeconstituents total dose range that needs to use generally can be about 0.001mg/kg/ days to about 200mg/kg/ days, preferably about 0.01mg/kg/ days to about 200mg/kg/ days.Unitary dose can contain the 0.05mg that has an appointment to about 1500mg activeconstituents, and every day can administration 1 time or repeatedly.The drug administration by injection (comprising intravenously, muscle, subcutaneous and parenteral injection) and the per daily dose of use infusion techniques can be about 0.01-200mg/kg.The day dosage regimen of rectum can be 0.01-200mg/kg (TBW).Transdermal administration need be kept per daily dose 0.01-200mg/kg.
Certainly, each patient's concrete predose depends on different factors with successive administration dosage, for example the activity of the particular compound of the illness character determined of diagnostician and seriousness, use, patient's age, patient's diet, administration time, application method, drug excretion rate, drug combination etc.The need therapeutic modality and the administration number of times of The compounds of this invention or its pharmacy acceptable salt can use the conventional treatment test to determine by those skilled in the art.
The compounds of this invention can be used for reaching by the patient who needs this treatment with the medicinal compositions of suitable preparation the pharmacological action of needs.For the object of the invention, the patient comprises the people for needing the Mammals of treatment particular disorder or disease.Therefore, the present invention includes and contain pharmaceutically acceptable carrier and the methods described herein compounds identified of pharmacy effective dose or the medicinal compositions of its pharmacy acceptable salt or ester.Pharmaceutically acceptable carrier is any carrier nontoxic and harmless relatively to the patient when being applicable to the concentration of activeconstituents useful effect, and any side effect of carrier can not damage the beneficial effect of activeconstituents like this.The pharmacy effective dose of compound is the dosage that the particular disorder of being treated is produced certain effect or plays a role.Utilize the method compounds identified introduced among the present invention can with pharmaceutically acceptable carrier with any effective regular dosage form (release immediately and the time release formulation of for example oral, parenteral medication, local application etc.) medication.
For oral medication, The compounds of this invention can be mixed with solid or liquid preparation, for example capsule, pill, tablet, dragee, lozenge, fusion agent, powder, solution, suspensoid or emulsion, and can prepare oral preparations according to the known method in preparation medicinal compositions field.Solid unit dosage form can be common hardness shell gelatine capsule agent or soft shell gelatin capsules agent, contains for example tensio-active agent, lubricant and inert filler such as lactose, sucrose, calcium phosphate and W-Gum.
In another embodiment, The compounds of this invention can prepare tablet with conventional tablet matrix (as lactose, sucrose and W-Gum) and following composition: tackiness agent, for example gum arabic, W-Gum or gelatin; Be used for making after the medication tablet burst apart dissolved disintegrating agent, for example yam starch, alginic acid, W-Gum and guar gum; Be used to improve the tablet and powder flowability and prevent that tablet from adhering to the lubricant of punch die and press surface, for example talcum powder, stearic acid, Magnesium Stearate, calcium stearate or Zinic stearas; Pigment; Tinting material; Being used to improve the tablet aesthetic property and making it easier is the seasonings that the patient accepted.The vehicle that is applicable to the liquid oral formulation comprises thinner, and for example water and alcohols (for example ethanol, benzylalcohol and polyoxyethylene glycol) add or do not add pharmaceutically acceptable tensio-active agent, suspension agent or emulsifying agent.Can contain the material that other is used as dressing or improves the physical form of dose unit.For example tablet, pill or capsule can be used shellac, sugar or this two kinds of raw material dressings.
Dispersible powder and particle are applicable to the preparation aqueous suspension.They are the mixture of activeconstituents and dispersion agent or wetting agent, suspension agent and one or more sanitass.The example of suitable dispersion agent or wetting agent and suspension agent is above being listed.Can also contain other vehicle, for example above-mentioned sweeting agent, seasonings and tinting material.
Medicinal compositions of the present invention also can be oil-in-water emulsion.Oil phase can be vegetables oil, for example the mixture of whiteruss or various plants oil.Suitable emulsifying agent can be (1) natural gum, for example gum arabic and tragacanth, (2) natural phospholipid, for example soybean phospholipid and Yelkin TTS, (3) lipid acid and hexitan deutero-ester or part ester, sorbitol monooleate for example, the condensation product of (4) described part ester and ethylene oxide, for example polyoxyethylene sorbitol monoleate.This emulsion can also contain sweeting agent and seasonings.
The oiliness suspensoid can followingly be prepared: activeconstituents is suspended in the vegetables oil, wherein for example peanut oil, sweet oil, sesame oil or Oleum Cocois of vegetables oil; Perhaps activeconstituents is suspended in the mineral oil, for example whiteruss.The oiliness suspensoid can contain thickening material, for example beeswax, solid paraffin or hexadecanol.The oiliness suspensoid can also contain one or more sanitass, for example ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl; One or more tinting materials; One or more seasoningss; One or more sweeting agents, for example sucrose or asccharin.
Can use agent of sweeting agent obtain syrup or elixir, for example glycerine, propylene glycol, sorbyl alcohol or sucrose.This class preparation can also contain negative catalyst, sanitas, seasonings and tinting material.
The compounds of this invention also can the parenteral medication, that is to say,, intravenously subcutaneous, muscle or intraperitoneal administration with described compound injection in acceptable diluent and the pharmaceutically acceptable carrier on physiology, described pharmaceutically acceptable carrier can be sterile liquid or liquid mixture, for example water, salt solution, aqueous glucose and relevant sugar soln; Unary alcohol, for example ethanol, Virahol or cetyl alcohol; Di-alcohols, for example propylene glycol or polyoxyethylene glycol; Aldehyde ketal class, for example 2,2-dimethyl-1,1-dioxolane-4-methyl alcohol; Ethers, for example poly(oxyethylene glycol) 400; Oil; Lipid acid; Fatty acid ester or glyceryl ester; Perhaps acetylize glycerin fatty acid ester; Wherein be added with or do not add pharmaceutically acceptable tensio-active agent (for example fatty acid salt or stain remover), suspension agent (for example pectin, carbomer, methylcellulose gum, Vltra tears or carboxymethyl cellulose) or emulsifying agent and other medicinal auxiliary.
The exemplary oil that can be used for parenteral formulation of the present invention has oil, animal oil, vegetables oil or synthetic oil, for example peanut oil, soybean oil, sesame oil, oleum gossypii seminis, Semen Maydis oil, sweet oil, vaseline and mineral oil.Suitable fatty acids comprises oleic acid, stearic acid and Unimac 5680.The suitable fatty acids ester has for example ethyl oleate and isopropyl myristate.Suitable fatty acids salt comprises fatty an alkali metal salt, ammonium salt and triethanolamine salt, and suitable stain remover comprises cationic detergent, for example dimethyl dialkyl ammonium halide, halogenated alkyl pyridine and acetate alkylamine; Anionic detergent, for example sulfuric ester of the sulphonate of alkyl, aryl and alkene, alkyl, alkene, ether and single glycerine and sulfosuccinic ester; Nonionic detergent, for example fatty amine oxide, Marlamid and polyoxyethylene polypropylene copolymer; Both sexes stain remover, for example alkyl-β-An Jibingsuan ester and 2-alkyl imidazoline quaternary ammonium salt and their mixture.
Parenteral composition solution of the present invention generally can contain the 0.5%-25% that has an appointment (weight) activeconstituents.Can also advantageously use sanitas and buffer reagent.In order to minimize or eliminate the hormesis to the injection site, this based composition can contain the nonionogenic tenside of the about 12-17 of hydrophilic-lipophilic balance (HLB).Surfactant content in this preparation is about 5%-15% (weight).Described tensio-active agent can have a kind of component of above-mentioned HLB, also can be the mixture of two or more components with described HLB.
The exemplary surfactants that is used for parenteral formulation has polyethylene Span class, for example the high molecular weight adducts of sorbitol monooleate and ethylene oxide and hydrophobic group (propylene oxide and propylene glycol condensation form).
Described medicinal compositions can be the aseptic injection water suspensoid.This suspensoid can be prepared according to currently known methods, uses suitable dispersant or wetting agent and suspension agent, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpolypyrrolidone, tragacanth and gum arabic; Disperse or wetting agent, it be possible naturally occurring phosphatide (for example Yelkin TTS), alkylene oxide and the condensation product (for example octadecanoic acid ester of polyethylene glycol) of condensation product (for example heptadecane vinyloxy group hexadecanol), ethylene oxide and the partial ester (by lipid acid and hexitol generation) of condensation product (for example stearic acid polyoxyethylene), ethylene oxide and the long chain aliphatic of lipid acid or the condensation product (for example polyoxyethylenesorbitan sorbitan monooleate) of ethylene oxide and partial ester (using the generation of lipid acid and hexitan).
Aseptic injection also can be nontoxicity parenteral acceptable diluent or solvent borne aseptic injection or suspensoid.Operable thinner and solvent for example have water, RingerShi solution and etc. open sodium chloride solution.In addition, sterile non-volatile oils is conventionally used as solvent or suspension medium.For this reason, any non-stimulated nonvolatile oil be can use, synthetic direactive glyceride or two glyceryl ester comprised.In addition, for example lipid acid such as oleic acid can be used for preparing injection.
The compounds of this invention also can use with suppository form, so that rectum is used described medicine.This composition can be prepared as follows: described medicine is mixed with suitable non-irritating excipient, and described vehicle is solid at normal temperatures, but be liquid under rectal temperature, therefore at rectum fusing release medicine.Such material has for example theobroma oil and polyoxyethylene glycol.
The preparation that another kind is used for the inventive method uses transdermal delivery device (" patch ").This transdermal patch can be used for continuous or discontinuous with manipulated variable infusion The compounds of this invention.The structure and the use of transmitting the transdermal patch of medicine are this area known (referring to for example U.S. Patent number 5,023,252, being attached to herein by reference).This patch can be prepared into continuously, pulsed or transmit medicine on demand.
May need maybe medicinal compositions must be imported in patient's body by mechanical doser.The structure and the use of transmitting the mechanical transfer device of medicine are that this area is known.The direct technology that medicine is applied directly to brain usually relates to puts into patient's ventricular system with the useful for drug delivery conduit, thereby walks around hemato encephalic barrier.A kind of such implantation transfer system that is used for medicine is transported to the body particular anatomical region is attached to herein by reference referring to U.S. Patent number 5,011,472.
The present composition also may must maybe need to contain acceptable adjustment composition on other conventional pharmaceutical, is commonly referred to as carrier or thinner.All The compounds of this invention can add antioxidant (for example xitix) or other suitable preservatives is preserved.Can use the ordinary method of the composition of this dosage forms of preparation.
The usual pharmaceutical composition that is suitable for preparing the composition of predetermined route of administration comprises: souring agent, such as but not limited to acetate, citric acid, fumaric acid, hydrochloric acid, nitric acid; Basifier is such as but not limited to ammonia soln, volatile salt, diethanolamine, monoethanolamine, potassium hydroxide, Sodium Tetraborate, yellow soda ash, sodium hydroxide, trolamine, trolamine.
Other pharmacy composition for example comprises (but being not limited thereto) sorbent material (for example Solka-floc and activated carbon); Aerosol propellant (for example carbonic acid gas, CCl 2F 2, F 2ClC-CClF 2And CClF 3); Air displacement agent (for example nitrogen and argon); Fungicidal sanitas (for example phenylformic acid, butyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, propylparaben, Sodium Benzoate); Antibiotic antiseptic (for example benzalkonium chloride, benzethonium chloride, phenylcarbinol, cetylpyridinium chloride, butylene-chlorohydrin, phenol, phenylethyl alcohol, Phenylmercurinitrate and thimerosal); Oxidation inhibitor (for example xitix, Ascorbyl Palmitate, BHA, 2,6 ditertiary butyl p cresol, Hypophosporous Acid, 50, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium sulfoxylate formaldehyde, Sodium Pyrosulfite); Binding substance (for example block polymer, natural and synthetic rubber, polyacrylic ester, urethane, silicones and styrene-butadiene copolymer); Buffer reagent (for example potassium metaphosphate, potassium primary phosphate, sodium acetate, Citric Acid, usp, Anhydrous Powder sodium and two hydration Trisodium Citrates); Carrier (for example syrup acacia, fragrant syrup, seimple elixir, cherry syrup, cocoa syrup, oranges and tangerines syrup, syrup, Semen Maydis oil, mineral oil, peanut oil, sesame oil, biocidal property sodium chloride injection and injection bacteriostatic water); Sequestrant (for example disodium ethylene diamine tetraacetate and ethylenediamine tetraacetic acid (EDTA)); Tinting material (FD﹠amp for example; C red No. 3, FD﹠amp; C red No. 20, FD﹠amp; C yellow No. 6, FD﹠amp; C blue No. 2, D﹠amp; C green No. 5, D﹠amp; Orange No. 5 of C, D﹠amp; Red No. 8 of C, caramel and ferric oxide); Finings (for example wilkinite); Emulsifying agent (but being not limited to gum arabic, cetomacrogol, hexadecanol, Zerol, Yelkin TTS, sorbitan monooleate, polyethylene (50) stearate); Encapsulants (for example gelatin and cellulose acetate phthalate); Flavouring agent (for example olium anisi, Oleum Cinnamomi, cocoa, menthol, orange-peel oil, oleum menthae piperitae and Vanillin); Wetting agent (for example glycerine, propylene glycol and Sorbitol Powder); Abrasive (for example mineral oil and glycerine); Oils (for example peanut oil, mineral oil, sweet oil, peanut oil, sesame oil and vegetables oil); Ointment base (for example lanolin, hydrophilic ointment, polyethylene glycol ointment, Vaseline, wetting ability Vaseline, simple Ointment, unguentum flavum and cold cream); Penetration enhancers (transdermal administration) (for example monohydroxy or polyhydroxy-alcohol, saturated or unsaturated fatty alcohol, saturated or unsaturated fatty acids ester, saturated or unsaturated dicarboxylic acid, volatile oil, phosphatidyl derivative, kephalin, terpenes, acid amides, ether, ketone and urea); Softening agent (for example diethyl phthalate and glycerine); Solvent (for example alcohol, Semen Maydis oil, Oleum Gossypii semen, glycerine, Virahol, mineral oil, oleic acid, peanut oil, purify waste water, water for injection, Injectable sterile water and flushing sterilized water); Stiffening agent (for example hexadecanol, spermaceti ester type waxes, Microcrystalline Wax, paraffin, stearyl alcohol, Chinese wax and cera flava); Suppository base (for example theobroma oil and polyoxyethylene glycol (mixture)); Tensio-active agent (for example benzalkonium chloride, nonoxinol 10, oxtoxynol 9, tween 80, sodium lauryl sulphate and sorbitan monopalmitin); Suspensoid (for example agar, wilkinite, carbomer, Xylo-Mucine, Natvosol, hydroxypropylcellulose, Vltra tears, kaolin, methylcellulose gum, tragakanta and veegum); Sweeting agent, for example aspartame, glucose, glycerine, mannitol, propylene glycol, soluble saccharin, Sorbitol Powder and sucrose); Tablet antitack agent (for example Magnesium Stearate and talcum powder); Tablet binder (for example gum arabic, Lalgine, Xylo-Mucine, compressible sugar, ethyl cellulose, gelatin, Liquid Glucose, methylcellulose gum, polyvidone and starch,pregelatinized); The thinner of tablet and capsule (for example secondary calcium phosphate, kaolin, lactose, mannitol, Microcrystalline Cellulose, Solka-floc, precipitated chalk, yellow soda ash, sodium phosphate, Sorbitol Powder and starch); Tablet coating agent (for example Liquid Glucose, Natvosol, hydroxypropylcellulose, Vltra tears, methylcellulose gum, ethyl cellulose, cellulose acetate phthalate and shellac); The direct compressible excipients of tablet (for example secondary calcium phosphate); Tablet disintegrant (for example Lalgine, calcium carboxymethylcellulose, Microcrystalline Cellulose, polacrilin potassium, sodiun alginate, Explotab and starch); Tablet glidant (for example colloid silica, W-Gum and talcum powder); Tablet lubricants (for example calcium stearate, Magnesium Stearate, mineral oil, stearic acid and Zinic stearas); The opacifying agent of tablets/capsules agent (for example titanium dioxide); Tablet rumbling compound (for example carnauba wax and Chinese wax); Thickening material (for example beeswax, hexadecanol and paraffin); Tonicity agents (for example glucose and sodium-chlor); Tackifier (for example Lalgine, wilkinite, carbomer, Xylo-Mucine, methylcellulose gum, polyvidone, sodiun alginate and tragakanta); And wetting agent (for example heptadecaethylene oxycetanol, Yelkin TTS, polyethylene Sorbitol Powder monooleate, polyoxyethylene Sorbitol Powder monooleate and polyoxyethylene stearate).
Can give with independent medicine or unite one or more other medicines to give by the aforesaid method compounds identified, described drug combination can not cause unacceptable side effect.For example The compounds of this invention can with known antiadipositas drug, antidiabetic drug or other indication medicine etc. and with the mixture and the combinatorial association medication of these medicines.
Also can use its free alkali form or composition forms, be used for research and diagnosis or with the reference standard etc. that performs an analysis by the aforesaid method compounds identified.Therefore, the present invention includes and contain inert support and significant quantity composition by aforesaid method compounds identified or its salt or ester.Inert support by not with the compound effects of being carried and to the carrying compound carrier be provided, transport instrument, any material of increase-volume, tracer material etc.The significant quantity of compound is meant particular procedure is produced certain result or applies the amount of certain influence.
The preparation that is fit to medications such as subcutaneous, vein, intramuscular; Suitable pharmaceutical carriers and the technology that is used to prepare with administration can be by any method preparation well-known in the art (referring to for example Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., the 20th edition, 2000).
Following example is used to illustrate the present invention, but should not be interpreted as any restriction to the scope of the invention.
Capsule
Capsule prepares with following material:
The compounds of this invention 40mg
Starch 109mg
Magnesium Stearate 1mg
Each component is mixed,, be filled into hard gelatine capsule then by suitable sieve aperture.
Tablet
Tablet prepares with following material:
The compounds of this invention 25mg
Microcrystalline Cellulose 200mg
Colloid silica 10mg
Stearic acid 5.0mg
Each component is mixed the back compacting form tablet.Can use suitable water-based and non-aqueous dressing to strengthen palatability, improve outward appearance and stability or postpone absorption.
Aseptic IV solution
The 5mg/ml solution of required The compounds of this invention is prepared with sterile water for injection, can regulate pH if desired.With of 1-2mg/ml concentration administration and among 60mins the IV infusion administration of above solution dilution to contain aseptic 5% glucose.
Intramuscular medication suspensoid
Prepare following intramuscular medication suspensoid:
The compounds of this invention 50mg/ml
Xylo-Mucine 5mg/ml
Tween 80 4mg/ml
Sodium-chlor 9mg/ml
Phenylcarbinol 9mg/ml
With this suspensoid intramuscular administration.
The hard-shell capsule agent
Prepare a large amount of unit capsules by two sections hard gelatine capsules of filling standard, the powdered activated composition of 100mg is housed in each capsule, 150mg lactose, 50mg Mierocrystalline cellulose and 6mg Magnesium Stearate.
Soft gelatin capsule
The mixture of preparation activeconstituents and digestible oil (for example soybean oil, Oleum Gossypii semen or sweet oil) is expelled to molten gelatin by volumetric pump then and forms the soft gelatin capsule agent that comprises the 100mg activeconstituents.Washing and dry capsule.Activeconstituents can be dissolved in preparation water-soluble pesticide mixture in the mixture of polyoxyethylene glycol, glycerine and Sorbitol Powder.
The directly tablets/capsules agent of Shi Fanging
These preparations are the solid oral dosage forms by ordinary method and novel method preparation.These unit are directly oral, and water does not directly dissolve and transmits medicine.Activeconstituents mixes in the liquid that comprises various compositions (for example sugar, gelatin, pectin and sweetener).By lyophilize and solid extraction technology aforesaid liquid is cured as solid tablet or capsule sheet.Medicinal compound can produce porous matrix with visco-elasticity and thermo-elasticity sugar and polymkeric substance or the compression of effervescent component, is used for discharging immediately and does not need water.
Those of ordinary skills be it is evident that and can carry out changes and improvements to the present invention under the situation of essence that does not break away from this paper and set forth or scope.

Claims (90)

1.一种式I化合物及其药学上可接受的盐：1. A compound of formula I and pharmaceutically acceptable salts thereof:
Figure C028186760002C1
Figure C028186760002C1
 其中in R为H或C1-C6烷基；R is H or C 1 -C 6 alkyl; R1为H、COOR、C3-C8环烷基或者R 1 is H, COOR, C 3 -C 8 cycloalkyl or C1-C6烷基、C2-C6链烯基或C1-C6烷氧基，各基团可以未被取代或被氟、亚甲二氧基苯基或苯基取代，其中苯基可以未被取代或被R6取代；C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy, each group may be unsubstituted or substituted by fluorine, methylenedioxyphenyl or phenyl, wherein Phenyl can be unsubstituted or substituted by R 6 ; R2为H、卤基或未被取代或被C1-C6烷氧基、氧代、氟取代的C1-C6烷基；或者R 2 is H, halo or C 1 -C 6 alkyl unsubstituted or substituted by C 1 -C 6 alkoxy, oxo, fluorine; or R2为苯基、呋喃基、噻吩基、吡咯基、吡啶基，各基团可以未被取代或被R6取代；R 2 is phenyl, furyl, thienyl, pyrrolyl, pyridyl, each group can be unsubstituted or substituted by R 6 ; R3为H、C1-C6烷基或者未被取代或被R6取代的苯基；R 3 is H, C 1 -C 6 alkyl or unsubstituted or substituted phenyl by R 6 ; X为O或S；X is O or S; R4为C1-C6烷基或C3-C8环烷基，两种基团均可以未被取代、或被氟、氧代或者未被取代或被C1-C6烷氧基或苯基取代的C1-C6烷氧基取代，其中苯基任选被R6取代；或者R 4 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, both groups can be unsubstituted, or fluorine, oxo or unsubstituted or C 1 -C 6 alkoxy or phenyl substituted C 1 -C 6 alkoxy substituted, wherein phenyl is optionally substituted by R 6 ; or 两种基团均可被以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R6取代；或者Both groups can be substituted by the following groups: phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, Imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiazolyl pyryl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, Indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, Quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl or 1,4-benzodioxanyl, each group can is unsubstituted or substituted by R6 ; or C1-C6烷基也可以被C3-C8环烷基或苯氧基取代，其中苯氧基可以未被取代或者被R6或以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R6取代；C 1 -C 6 alkyl can also be substituted by C 3 -C 8 cycloalkyl or phenoxy, where phenoxy can be unsubstituted or substituted by R 6 or the following groups: phenyl, naphthyl, furyl , Thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholine Base, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl , benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, di Hydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, each group can be unsubstituted or substituted by R 6 ; 或者or R4为苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基， R4 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxa Azolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl , pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, dihydroindolyl, indazolyl , benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, Quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, 各基团可以未被取代或被R6或以下基团取代：苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、苯并间二氧杂环戊烯基、二氢苯并呋喃基、吲哚基、嘧啶基或苯氧基，各基团可以未被取代或被R6取代；Each group can be unsubstituted or substituted by R or the following groups: phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole Base, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , benzodioxolyl, dihydrobenzofuryl, indolyl, pyrimidinyl or phenoxy, each group can be unsubstituted or substituted by R 6 ; R5为H、卤基或任选被氧代取代的C1-C6烷基；R 5 is H, halo or C 1 -C 6 alkyl optionally substituted by oxo; R6为卤基、CF3、任选被氧代或羟基取代的C1-C6烷基或者任选被氟取代的C1-C6烷氧基。R 6 is halo, CF 3 , C 1 -C 6 alkyl optionally substituted by oxo or hydroxy, or C 1 -C 6 alkoxy optionally substituted by fluorine. 2.权利要求1的化合物及其药学上可接受的盐，其中2. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein R为H或C1-C6烷基；R is H or C 1 -C 6 alkyl; R1为H、COOR、C3-C8环烷基或者R 1 is H, COOR, C 3 -C 8 cycloalkyl or C1-C6烷基、C2-C6链烯基或C1-C6烷氧基，各基团可以未被取代或被氟、亚甲二氧基苯基或苯基取代，其中苯基可以未被取代或被R6取代；C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy, each group may be unsubstituted or substituted by fluorine, methylenedioxyphenyl or phenyl, wherein Phenyl can be unsubstituted or substituted by R 6 ; R2为H、卤基或未被取代或被C1-C6烷氧基、氧代、氟取代的C1-C6烷基；或者R 2 is H, halo or C 1 -C 6 alkyl unsubstituted or substituted by C 1 -C 6 alkoxy, oxo, fluorine; or R2为苯基、呋喃基、噻吩基、吡咯基、吡啶基，各基团可以未被取代或被R6取代；R 2 is phenyl, furyl, thienyl, pyrrolyl, pyridyl, each group can be unsubstituted or substituted by R 6 ; R3为H、C1-C6烷基或者未被取代或被R6取代的苯基；R 3 is H, C 1 -C 6 alkyl or unsubstituted or substituted phenyl by R 6 ; X为O；X is O; R4为C1-C6烷基或C3-C8环烷基，两种基团均可以未被取代、或被氟、氧代或者未被取代或被C1-C6烷氧基或苯基取代的C1-C6烷氧基取代，其中苯基任选被R6取代；或者R 4 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, both groups can be unsubstituted, or fluorine, oxo or unsubstituted or C 1 -C 6 alkoxy or phenyl substituted C 1 -C 6 alkoxy substituted, wherein phenyl is optionally substituted by R 6 ; or 两种基团均可被以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R6取代；或者Both groups can be substituted by the following groups: phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, Imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiazolyl pyryl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, Indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, Quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl or 1,4-benzodioxanyl, each group can is unsubstituted or substituted by R6 ; or C1-C6烷基也可以被C3-C8环烷基或苯氧基取代，其中苯氧基可以未被取代或者被R6或以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R6取代；C 1 -C 6 alkyl can also be substituted by C 3 -C 8 cycloalkyl or phenoxy, where phenoxy can be unsubstituted or substituted by R 6 or the following groups: phenyl, naphthyl, furyl , Thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholine Base, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl , benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, di Hydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, each group can be unsubstituted or substituted by R 6 ; 或者or R4为苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基， R4 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxa Azolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl , pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, dihydroindolyl, indazolyl , benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, Quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, 各基团可以未被取代或被R6或以下基团取代：苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、苯并间二氧杂环戊烯基、二氢苯并呋喃基、吲哚基、嘧啶基或苯氧基，各基团可以未被取代或被R6取代；Each group can be unsubstituted or substituted by R or the following groups: phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole Base, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , benzodioxolyl, dihydrobenzofuryl, indolyl, pyrimidinyl or phenoxy, each group can be unsubstituted or substituted by R 6 ; R5为H、卤基或任选被氧代取代的C1-C6烷基；R 5 is H, halo or C 1 -C 6 alkyl optionally substituted by oxo; R6为卤基、CF3、任选被氧代或羟基取代的C1-C6烷基或者任选被氟取代的C1-C6烷氧基。R 6 is halo, CF 3 , C 1 -C 6 alkyl optionally substituted by oxo or hydroxy, or C 1 -C 6 alkoxy optionally substituted by fluorine. 3.权利要求1的化合物及其药学上可接受的盐，其中3. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein R为H或C1-C6烷基；R is H or C 1 -C 6 alkyl; R1为H、COOR、C3-C8环烷基或者R 1 is H, COOR, C 3 -C 8 cycloalkyl or C1-C6烷基、C2-C6链烯基或C1-C6烷氧基，各基团可以未被取代或被氟、亚甲二氧基苯基或苯基取代，其中苯基可以未被取代或被R6取代；C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy, each group may be unsubstituted or substituted by fluorine, methylenedioxyphenyl or phenyl, wherein Phenyl can be unsubstituted or substituted by R 6 ; R2为H、卤基或未被取代或被C1-C6烷氧基、氧代、氟取代的C1-C6烷基；或者R 2 is H, halo or C 1 -C 6 alkyl unsubstituted or substituted by C 1 -C 6 alkoxy, oxo, fluorine; or R2为苯基、呋喃基、噻吩基、吡咯基、吡啶基，各基团可以未被取代或被R6取代；R 2 is phenyl, furyl, thienyl, pyrrolyl, pyridyl, each group can be unsubstituted or substituted by R 6 ; R3为H、C1-C6烷基或者未被取代或被R6取代的苯基；R 3 is H, C 1 -C 6 alkyl or unsubstituted or substituted phenyl by R 6 ; X为S；X is S; R4为C1-C6烷基或C3-C8环烷基，两种基团均可以未被取代、或被氟、氧代或者未被取代或被C1-C6烷氧基或苯基取代的C1-C6烷氧基取代，其中苯基任选被R6取代；或者R 4 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, both groups can be unsubstituted, or fluorine, oxo or unsubstituted or C 1 -C 6 alkoxy or phenyl substituted C 1 -C 6 alkoxy substituted, wherein phenyl is optionally substituted by R 6 ; or 两种基团均可被以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R6取代；或者Both groups can be substituted by the following groups: phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, Imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiazolyl pyryl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, Indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, Quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl or 1,4-benzodioxanyl, each group can is unsubstituted or substituted by R6 ; or C1-C6烷基也可以被C3-C8环烷基或苯氧基取代，其中苯氧基可以未被取代或者被R6或以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R6取代；C 1 -C 6 alkyl can also be substituted by C 3 -C 8 cycloalkyl or phenoxy, where phenoxy can be unsubstituted or substituted by R 6 or the following groups: phenyl, naphthyl, furyl , Thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholine Base, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl , benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, di Hydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, each group can be unsubstituted or substituted by R 6 ; 或者or R4为苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基， R4 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxa Azolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl , pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, dihydroindolyl, indazolyl , benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, Quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, 各基团可以未被取代或被R6或以下基团取代：苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、苯并间二氧杂环戊烯基、二氢苯并呋喃基、吲哚基、嘧啶基或苯氧基，各基团可以未被取代或被R6取代；Each group can be unsubstituted or substituted by R or the following groups: phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole Base, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , benzodioxolyl, dihydrobenzofuryl, indolyl, pyrimidinyl or phenoxy, each group can be unsubstituted or substituted by R 6 ; R5为H、卤基或任选被氧代取代的C1-C6烷基；R 5 is H, halo or C 1 -C 6 alkyl optionally substituted by oxo; R6为卤基、CF3、任选被氧代或羟基取代的C1-C6烷基或者任选被氟取代的C1-C6烷氧基。R 6 is halo, CF 3 , C 1 -C 6 alkyl optionally substituted by oxo or hydroxy, or C 1 -C 6 alkoxy optionally substituted by fluorine. 4.权利要求1的化合物及其药学上可接受的盐，其中4. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein R为H；R is H; R1为H、COOR、C3-C8环烷基或者R 1 is H, COOR, C 3 -C 8 cycloalkyl or C1-C6烷基、C2-C6链烯基或C1-C6烷氧基，各基团可以未被取代或被氟、亚甲二氧基苯基或苯基取代，其中苯基可以未被取代或被R6取代；C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy, each group may be unsubstituted or substituted by fluorine, methylenedioxyphenyl or phenyl, wherein Phenyl can be unsubstituted or substituted by R 6 ; R2为H、卤基或未被取代或被C1-C6烷氧基、氧代、氟取代的C1-C6烷基；R 2 is H, halogen or C 1 -C 6 alkyl that is unsubstituted or substituted by C 1 -C 6 alkoxy, oxo, or fluorine; R3为H、C1-C6烷基或者未被取代或被R6取代的苯基；R 3 is H, C 1 -C 6 alkyl or unsubstituted or substituted phenyl by R 6 ; X为S；X is S; R4为苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基， R4 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxa Azolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl , pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, dihydroindolyl, indazolyl , benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, Quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, 各基团可以未被取代或被R6或以下基团取代：苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、苯并间二氧杂环戊烯基、二氢苯并呋喃基、吲哚基、嘧啶基或苯氧基，各基团可以未被取代或被R6取代；Each group can be unsubstituted or substituted by R or the following groups: phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole Base, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , benzodioxolyl, dihydrobenzofuryl, indolyl, pyrimidinyl or phenoxy, each group can be unsubstituted or substituted by R 6 ; R5为H、卤基或任选被氧代取代的C1-C6烷基；R 5 is H, halo or C 1 -C 6 alkyl optionally substituted by oxo; R6为卤基、CF3、任选被氧代或羟基取代的C1-C6烷基或者任选被氟取代的C1-C6烷氧基。R 6 is halo, CF 3 , C 1 -C 6 alkyl optionally substituted by oxo or hydroxy, or C 1 -C 6 alkoxy optionally substituted by fluorine. 5.权利要求1的化合物及其药学上可接受的盐，其中5. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein R为H；R is H; R1为H、COOR、C3-C8环烷基或者R 1 is H, COOR, C 3 -C 8 cycloalkyl or C1-C6烷基、C2-C6链烯基或C1-C6烷氧基，各基团可以未被取代或被氟、亚甲二氧基苯基或苯基取代，其中苯基可以未被取代或被R6取代；C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy, each group may be unsubstituted or substituted by fluorine, methylenedioxyphenyl or phenyl, wherein Phenyl can be unsubstituted or substituted by R 6 ; R2为H、卤基或未被取代或被C1-C6烷氧基、氧代、氟取代的C1-C6烷基；R 2 is H, halogen or C 1 -C 6 alkyl that is unsubstituted or substituted by C 1 -C 6 alkoxy, oxo, or fluorine; R3为H、C1-C6烷基或者未被取代或被R6取代的苯基；R 3 is H, C 1 -C 6 alkyl or unsubstituted or substituted phenyl by R 6 ; X为O；X is O; R4为苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基， R4 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxa Azolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl , pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, dihydroindolyl, indazolyl , benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, Quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, 各基团可以未被取代或被R6或以下基团取代：苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、苯并间二氧杂环戊烯基、二氢苯并呋喃基、吲哚基、嘧啶基或苯氧基，各基团可以未被取代或被R6取代；Each group can be unsubstituted or substituted by R or the following groups: phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole Base, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , benzodioxolyl, dihydrobenzofuryl, indolyl, pyrimidinyl or phenoxy, each group can be unsubstituted or substituted by R 6 ; R5为H、卤基或任选被氧代取代的C1-C6烷基；R 5 is H, halo or C 1 -C 6 alkyl optionally substituted by oxo; R6为卤基、CF3、任选被氧代或羟基取代的C1-C6烷基或者任选被氟取代的C1-C6烷氧基。R 6 is halo, CF 3 , C 1 -C 6 alkyl optionally substituted by oxo or hydroxy, or C 1 -C 6 alkoxy optionally substituted by fluorine. 6.权利要求1的化合物及其药学上可接受的盐，其中6. The compound of claim 1 and pharmaceutically acceptable salt thereof, wherein R为H；R is H; R1为H、COOR、C3-C8环烷基或者R 1 is H, COOR, C 3 -C 8 cycloalkyl or C1-C6烷基、C2-C6链烯基或C1-C6烷氧基，各基团可以未被取代或被氟、亚甲二氧基苯基或苯基取代，其中苯基可以未被取代或被R6取代；C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy, each group may be unsubstituted or substituted by fluorine, methylenedioxyphenyl or phenyl, wherein Phenyl can be unsubstituted or substituted by R 6 ; R2为苯基、呋喃基、噻吩基、吡咯基、吡啶基，各基团可以未被取代或被R6取代；R 2 is phenyl, furyl, thienyl, pyrrolyl, pyridyl, each group can be unsubstituted or substituted by R 6 ; R3为H、C1-C6烷基或者未被取代或被R6取代的苯基；R 3 is H, C 1 -C 6 alkyl or unsubstituted or substituted phenyl by R 6 ; X为O；X is O; R4为C1-C6烷基或C3-C8环烷基，两种基团均可以未被取代、或被氟、氧代或者未被取代或被C1-C6烷氧基或苯基取代的C1-C6烷氧基取代，其中苯基任选被R6取代；或者R 4 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, both groups can be unsubstituted, or fluorine, oxo or unsubstituted or C 1 -C 6 alkoxy or phenyl substituted C 1 -C 6 alkoxy substituted, wherein phenyl is optionally substituted by R 6 ; or 两种基团均可被以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R6取代；或者Both groups can be substituted by the following groups: phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, Imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiazolyl pyryl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, Indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, Quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl or 1,4-benzodioxanyl, each group can is unsubstituted or substituted by R6 ; or C1-C6烷基也可以被C3-C8环烷基或苯氧基取代，其中苯氧基可以未被取代或者被R6或以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R6取代；C 1 -C 6 alkyl can also be substituted by C 3 -C 8 cycloalkyl or phenoxy, where phenoxy can be unsubstituted or substituted by R 6 or the following groups: phenyl, naphthyl, furyl , Thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholine Base, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl , benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, di Hydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, each group can be unsubstituted or substituted by R 6 ; 或者or R4为苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基， R4 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxa Azolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl , pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, dihydroindolyl, indazolyl , benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, Quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, 各基团可以未被取代或被R6或以下基团取代：苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、苯并间二氧杂环戊烯基、二氢苯并呋喃基、吲哚基、嘧啶基或苯氧基，各基团可以未被取代或被R6取代；Each group can be unsubstituted or substituted by R or the following groups: phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole Base, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , benzodioxolyl, dihydrobenzofuryl, indolyl, pyrimidinyl or phenoxy, each group can be unsubstituted or substituted by R 6 ; R5为H、卤基或任选被氧代取代的C1-C6烷基；R 5 is H, halo or C 1 -C 6 alkyl optionally substituted by oxo; R6为卤基、CF3、任选被氧代或羟基取代的C1-C6烷基或者任选被氟取代的C1-C6烷氧基。R 6 is halo, CF 3 , C 1 -C 6 alkyl optionally substituted by oxo or hydroxy, or C 1 -C 6 alkoxy optionally substituted by fluorine. 7.权利要求1的化合物，其中C-1′为S构型或R构型。7. The compound of claim 1, wherein C-1' is in the S configuration or the R configuration. 8.权利要求1的化合物，其中C-1′和C-2构型选自以下情况：C-1′为R，C-2为R；C-1′为R，C-2为S；C-1′为S，C-2为S；以及C-1′为S，C-2为R。8. The compound of claim 1, wherein the C-1' and C-2 configurations are selected from the following situations: C-1' is R, C-2 is R; C-1' is R, and C-2 is S; C-1' is S, C-2 is S; and C-1' is S, C-2 is R. 9.权利要求1的化合物，所述化合物选自以下化合物：9. The compound of claim 1 selected from the group consisting of: 5-{2-[2-(4-乙基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-Ethylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-(2-{5-甲基-2-[4-(三氟甲基)苯基]-1，3-噁唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基乙酸；5-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1H -inden-1-ylacetic acid; 5-{2-[5-甲基-2-(2-萘基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[5-Methyl-2-(2-naphthyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl acetic acid; 5-{2-[2-(4-叔丁基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-tert-butylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-ylacetic acid; 5-{2-[2-(4-丁基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-Butylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[2-(3，4-二甲基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3,4-Dimethylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-ylacetic acid; 5-{2-[2-(1-苯并噻吩-2-基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(1-Benzothiophen-2-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-ylacetic acid; 5-{2-[2-(4-异丙基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-Isopropylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-ylacetic acid; 5-[2-(2-环戊基-5-甲基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基乙酸；5-[2-(2-cyclopentyl-5-methyl-1,3-oxazol-4-yl)ethoxy]-2,3-dihydro-1H-inden-1-ylacetic acid; 5-{2-[2-(3-氟-4-甲基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3-fluoro-4-methylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H -inden-1-ylacetic acid; 5-{2-[2-(4-氟苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸。5-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1- Glycolic acid. 10.权利要求9的化合物，其中C-1′为S构型或R构型。10. The compound of claim 9, wherein C-1' is in the S configuration or the R configuration. 11.权利要求1的化合物，所述化合物选自以下化合物：11. The compound of claim 1 selected from the group consisting of: 2-(5-{2-[2-(4-乙基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丙酸；2-(5-{2-[2-(4-Ethylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-yl) propanoic acid; 2-(5-{2-[2-(3，4-二氯苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丙酸；2-(5-{2-[2-(3,4-dichlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro- 1H-inden-1-yl)propionic acid; 2-(5-(2-{5-甲基-2-[4-(三氟甲基)苯基]-1，3-噁唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基)丙酸；2-(5-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-di Hydrogen-1H-inden-1-yl)propanoic acid; 2-(5-{2-[2-(4-甲氧基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丙酸；2-(5-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H -inden-1-yl)propionic acid; 2-(5-{2-[2-(4-乙基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丙酸；2-(5-{2-[2-(4-Ethylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-yl) propanoic acid; 2-(5-{2-[2-(3，4-二甲基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丙酸；2-(5-{2-[2-(3,4-dimethylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro -1H-inden-1-yl)propionic acid; 2-(5-{2-[2-(4-甲氧基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丙酸。2-(5-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H -inden-1-yl)propionic acid. 12.权利要求11的化合物，其中C-1′和C-2的构型选自以下情况：C-1′为R，C-2为R；C-1′为R，C-2为S；C-1′为S，C-2为S；以及C-1′为S，C-2为R。12. The compound of claim 11, wherein the configuration of C-1' and C-2 is selected from the following situations: C-1' is R, C-2 is R; C-1' is R, and C-2 is S ; C-1' is S, C-2 is S; and C-1' is S, C-2 is R. 13.权利要求1的化合物，所述化合物选自以下化合物：13. The compound of claim 1 selected from the group consisting of: 5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基乙酸；5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-2,3-dihydro-1H-inden-1-ylacetic acid; 5-[2-(5-甲基-2-苯基-1，3-噻唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基乙酸；5-[2-(5-Methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]-2,3-dihydro-1H-inden-1-ylacetic acid; 5-{2-[2-(4-甲氧基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-Methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-ylacetic acid; 5-{2-[2-(3-甲氧基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3-Methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-ylacetic acid; 5-{2-[2-(1，3-苯并二噁茂-5-基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(1,3-benzodioxol-5-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-di Hydrogen-1H-inden-1-ylacetic acid; 5-{2-[5-甲基-2-(4-甲基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[5-Methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[2-(3-氟苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1- Glycolic acid; 5-{2-[2-(4-氟-3-甲基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-fluoro-3-methylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H -inden-1-ylacetic acid; 5-[2-(5-乙基-2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基乙酸；5-[2-(5-Ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-2,3-dihydro-1H-inden-1-ylacetic acid; 5-{2-[2-(3，4-二氯苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3,4-Dichlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-ylacetic acid; 5-{2-[2-(1，1′-联苯基-4-基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(1,1′-biphenyl-4-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro -1H-inden-1-ylacetic acid; 5-{2-[2-(1，3-苯并二噁茂-5-基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(1,3-benzodioxol-5-yl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro -1H-inden-1-ylacetic acid; 5-{2-[2-(4-甲氧基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-(2-{5-甲基-2-[4-(三氟甲基)苯基]-1，3-噻唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基乙酸；5-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}ethoxy)-2,3-dihydro-1H- Inden-1-ylacetic acid; 5-{2-[2-(4-氰基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-cyanophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1- Glycolic acid; 5-{2-[2-(4-异丙基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-isopropylphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[2-(3-氯苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3-Chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1- Glycolic acid; 5-{2-[2-(4-氰基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-cyanophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[2-(3-氰基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3-cyanophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[2-(4-氯苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-Chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1- Glycolic acid; 5-(2-{5-甲基-2-[3-(三氟甲基)苯基]-1，3-噁唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基乙酸；5-(2-{5-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1H -inden-1-ylacetic acid; 5-{2-[2-(3-氯-4-氟苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3-Chloro-4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-ylacetic acid; 5-{2-[2-(3，4-二氯苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3,4-Dichlorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-ylacetic acid; 5-{2-[2-(4-氟苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl acetic acid; 5-{2-[2-(3，4-二甲基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3,4-Dimethylphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-ylacetic acid; 5-{2-[2-(4-乙酰基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-Acetylphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1- Glycolic acid; 5-{2-[2-(3-氨基-4-甲基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸三氟乙酸盐；5-{2-[2-(3-amino-4-methylphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-ylacetic acid trifluoroacetate; 5-{2-[2-(2-氟苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(2-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl acetic acid; 5-{2-[2-(4-氯苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-Chlorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl acetic acid; 5-{2-[2-(4-乙氧基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(4-ethoxyphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[2-(3，4-二甲氧基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3,4-dimethoxyphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-ylacetic acid; 5-{2-[5-甲基-2-(3-甲基苯基)-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[5-Methyl-2-(3-methylphenyl)-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1- Glycolic acid; 5-(2-{5-甲基-2-[3-(三氟甲基)苯基]-1，3-噻唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基乙酸；5-(2-{5-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}ethoxy)-2,3-dihydro-1H- Inden-1-ylacetic acid; 5-{2-[2-(3-氟苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl acetic acid; 5-{2-[2-(3，5-二甲基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3,5-Dimethylphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-ylacetic acid; 5-(2-{5-甲基-2-[4-(三氟甲氧基)苯基]-1，3-噻唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基乙酸；5-(2-{5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}ethoxy)-2,3-dihydro-1H -inden-1-ylacetic acid; 5-{2-[2-(3-甲氧基苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[2-(1，1′-联苯基-4-基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[2-(1,1′-biphenyl-4-yl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro- 1H-inden-1-ylacetic acid; 5-{2-[5-乙基-2-(4-乙基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[5-Ethyl-2-(4-ethylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[5-乙基-2-(4-甲基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[5-Ethyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene-1 - Glycolic acid; 5-{2-[5-乙基-2-(4-甲氧基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基乙酸；5-{2-[5-Ethyl-2-(4-methoxyphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-ylacetic acid; 5-(2-{2-[4′-(羟基甲基)-1，1′-联苯基-4-基]-5-甲基-1，3-噁唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基乙酸；5-(2-{2-[4'-(hydroxymethyl)-1,1'-biphenyl-4-yl]-5-methyl-1,3-oxazol-4-yl}ethoxy base)-2,3-dihydro-1H-inden-1-ylacetic acid; 5-(2-{2-[4-(5-乙酰基-2-噻吩基)苯基]-5-甲基-1，3-噁唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基乙酸；5-(2-{2-[4-(5-acetyl-2-thienyl)phenyl]-5-methyl-1,3-oxazol-4-yl}ethoxy)-2,3 - dihydro-1H-inden-1-ylacetic acid; 5-(2-{2-[3-(1H-吲哚-5-基)苯基]-5-甲基-1，3-噁唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基乙酸；5-(2-{2-[3-(1H-indol-5-yl)phenyl]-5-methyl-1,3-oxazol-4-yl}ethoxy)-2,3- Dihydro-1H-inden-1-ylacetic acid; (5-{2-[2-(3-氟-4-甲基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)乙酸；(5-{2-[2-(3-fluoro-4-methylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro- 1H-inden-1-yl)acetic acid; (-5-{2-[5-甲基-2-(3-甲基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)乙酸。(-5-{2-[5-methyl-2-(3-methylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-yl) acetic acid. 14.权利要求13的化合物，其中C-1′为S构型或R构型。14. The compound of claim 13, wherein C-1' is in the S configuration or the R configuration. 15.权利要求1的化合物，所述化合物选自以下化合物：15. The compound of claim 1 selected from the group consisting of: 2-{5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基}丁酸；2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl} butyric acid; 3-乙氧基-2-{5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基}-3-氧代丙酸；3-Ethoxy-2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-2,3-dihydro-1H- Inden-1-yl}-3-oxopropionic acid; 2-(5-{2-[5-甲基-2-(4-甲基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丙酸；2-(5-{2-[5-Methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-yl) propanoic acid; 2-(5-{2-[5-甲基-2-(4-甲基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[5-Methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-yl) butanoic acid; 4-甲基-2-(5-{2-[5-甲基-2-(4-甲基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)戊酸；4-methyl-2-(5-{2-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3- Dihydro-1H-inden-1-yl)pentanoic acid; 2-{5-[2-(5-乙基-2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基}丁酸；2-{5-[2-(5-Ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl} butyric acid; 2-(5-{2-[2-(4-氯苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(4-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-yl) butanoic acid; 2-(5-{2-[5-甲基-2-(3-甲基苯基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[5-Methyl-2-(3-methylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-yl) butanoic acid; 2-(5-{2-[2-(4-甲氧基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H -inden-1-yl) butanoic acid; 2-(5-{2-[2-(3，4-二氯苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(3,4-dichlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro- 1H-inden-1-yl)butanoic acid; 2-(5-{2-[5-甲基-2-(2-萘基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[5-Methyl-2-(2-naphthyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-yl) butanoic acid; 2-(5-{2-[5-甲基-2-(1-萘基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[5-Methyl-2-(1-naphthyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-yl) butanoic acid; 2-(5-{2-[2-(4-氟苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-yl) butanoic acid; 2-(5-{2-[2-(3-氯苯基)-5-甲基-1，3-噻唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(3-chlorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2,3-dihydro-1H-indene- 1-yl) butanoic acid; 2-(5-{2-[2-环戊基-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二-氢-1H-茚-1-基)丁酸；2-(5-{2-[2-cyclopentyl-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-di-hydro-1H-indene-1- base) butanoic acid; 2-(5-{2-[2-环己基-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-Cyclohexyl-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl) butyric acid; 2-(5-{2-[2-(3-甲氧基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H -inden-1-yl) butanoic acid; 2-(5-{2-[2-(4-乙基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(4-Ethylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-yl) butanoic acid; 2-(5-{2-[2-(1-苯并噻吩-2-基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(1-benzothiophen-2-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro -1H-inden-1-yl)butanoic acid; 2-[5-(2-{5-甲基-2-[3-(三氟甲基)苯基]-1，3-噁唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基]丁酸；2-[5-(2-{5-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-di Hydrogen-1H-inden-1-yl]butanoic acid; 2-(5-{2-[2-(4-叔丁基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(4-tert-butylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H -inden-1-yl) butanoic acid; 2-(5-{2-[2-(3-氟苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(3-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-yl) butanoic acid; 2-(5-{2-[2-(4-异丙基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(4-isopropylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H -inden-1-yl) butanoic acid; 2-(5-{2-[2-(1，3-苯并二噁茂-5-基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(1,3-benzodioxol-5-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2, 3-dihydro-1H-inden-1-yl) butanoic acid; 2-{6-[2-(2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基}丁酸；2-{6-[2-(2-Phenyl-1,3-oxazol-4-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl}butanoic acid; 2-(5-{2-[2-(3，4-二氟苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(3,4-difluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro- 1H-inden-1-yl) butanoic acid; 2-[5-(2-{5-甲基-2-[4-(三氟甲基)苯基]-1，3-噁唑-4-基}乙氧基)-2，3-二氢-1H-茚-1-基]丁酸；2-[5-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-di Hydrogen-1H-inden-1-yl]butanoic acid; 2-(5-{2-[5-甲基-2-(苯氧基甲基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[5-Methyl-2-(phenoxymethyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-indene -1-yl) butanoic acid; 2-(5-{2-[2-(4-氟-3-甲基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1-茚-1-基)丁酸；2-(5-{2-[2-(4-fluoro-3-methylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-di Hydrogen-1-inden-1-yl) butanoic acid; 2-(5-{2-[2-(3-氟-4-甲基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(3-fluoro-4-methylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-di Hydrogen-1H-inden-1-yl) butanoic acid; 2-(5-{2-[2-(4-丁基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(4-Butylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H- Inden-1-yl) butanoic acid; 2-(5-{2-[2-(3，4-二甲基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[2-(3,4-dimethylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro -1H-inden-1-yl)butanoic acid; 2-(5-{2-[5-甲基-2-(4-氯苯氧基甲基)-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸；2-(5-{2-[5-methyl-2-(4-chlorophenoxymethyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro- 1H-inden-1-yl) butanoic acid; 2-{6-氯-5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基}丁酸；2-{6-chloro-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-2,3-dihydro-1H-indene- 1-yl}butanoic acid; 2-{5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-6-苯基-2，3-二氢-1H-茚-1-基}丁酸；2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-6-phenyl-2,3-dihydro-1H-indene -1-yl}butanoic acid; 2-{6-(4-氯苯基)-5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基}丁酸；2-{6-(4-chlorophenyl)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-2,3-di Hydrogen-1H-inden-1-yl}butanoic acid; 2-{6-(4-甲氧基苯基)-5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-2，3-二氢-1H-茚-1-基}丁酸；2-{6-(4-methoxyphenyl)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-2,3 - dihydro-1H-inden-1-yl}butanoic acid; 2-(5-{2-[2-(2，3-二氢-1-苯并呋喃-6-基)-5-甲基-1，3-噁唑-4-基]乙氧基}-2，3-二氢-1H-茚-1-基)丁酸。2-(5-{2-[2-(2,3-dihydro-1-benzofuran-6-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy} -2,3-Dihydro-1H-inden-1-yl)butanoic acid. 16.权利要求15的化合物，其中C-1′和C-2构型选自以下情况：C-1′为R，C-2为R；C-1′为R，C-2为S；C-1′为S，C-2为S；以及C-1′为S，C-2为R。16. The compound of claim 15, wherein the C-1' and C-2 configurations are selected from the group consisting of: C-1' is R, C-2 is R; C-1' is R, and C-2 is S; C-1' is S, C-2 is S; and C-1' is S, C-2 is R. 17.一种式III化合物及其盐：17. A compound of formula III and salts thereof:
Figure C028186760020C1
Figure C028186760020C1
 其中in R为H或C1-C6烷基；R is H or C 1 -C 6 alkyl; R1为H、COOR、C3-C8环烷基或者R 1 is H, COOR, C 3 -C 8 cycloalkyl or C1-C6烷基、C2-C6链烯基或C1-C6烷氧基，各基团可以未被取代或被氟、亚甲二氧基苯基或苯基取代，其中苯基可以未被取代或被R6取代；C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy, each group may be unsubstituted or substituted by fluorine, methylenedioxyphenyl or phenyl, wherein Phenyl can be unsubstituted or substituted by R 6 ; R2为H、卤基或未被取代或被C1-C6烷氧基、氧代、氟取代的C1-C6烷基；或者R 2 is H, halo or C 1 -C 6 alkyl unsubstituted or substituted by C 1 -C 6 alkoxy, oxo, fluorine; or R2为苯基、呋喃基、噻吩基、吡咯基、吡啶基，各基团可以未被取代或被R6取代；R 2 is phenyl, furyl, thienyl, pyrrolyl, pyridyl, each group can be unsubstituted or substituted by R 6 ; R3为H、C1-C6烷基或者未被取代或被R6取代的苯基；R 3 is H, C 1 -C 6 alkyl or unsubstituted or substituted phenyl by R 6 ; R5为卤基或任选被氧代取代的C1-C6烷基；R 5 is halo or C 1 -C 6 alkyl optionally substituted by oxo; R6为卤基、CF3、任选被氧代或羟基取代的C1-C6烷基或者任选被氟取代的C1-C6烷氧基；R 6 is halo, CF 3 , C 1 -C 6 alkyl optionally substituted by oxo or hydroxy, or C 1 -C 6 alkoxy optionally substituted by fluorine; R7为H、任选被苯基或氧代取代的C1-C6烷基、C1-C6三烷基甲硅烷基、芳基烷基甲硅烷基、COR8、COOR8；R 7 is H, C 1 -C 6 alkyl optionally substituted by phenyl or oxo, C 1 -C 6 trialkylsilyl, arylalkylsilyl, COR 8 , COOR 8 ; R8为C1-C6烷基或任选被C1-C6烷基、卤基或硝基取代的苯基。R 8 is C 1 -C 6 alkyl or phenyl optionally substituted by C 1 -C 6 alkyl, halo or nitro. 18.一种制备式V化合物的方法：18. A method for preparing a compound of formula V:
Figure C028186760021C1
Figure C028186760021C1
 所述方法包括在氢源和催化剂存在下立体有择氢化下式IV化合物的步骤：The method comprises the step of stereoselectively hydrogenating the following compound of formula IV in the presence of a hydrogen source and a catalyst:
Figure C028186760021C2
Figure C028186760021C2
 其中in R9为任选被氟取代的甲氧基；C2-C6烷氧基、C1-C6烷基或C4-C8环烷基，各基团任选被氟、亚甲二氧基苯基或任选被R13取代的苯基取代；R 9 is methoxy optionally substituted by fluorine; C 2 -C 6 alkoxy, C 1 -C 6 alkyl or C 4 -C 8 cycloalkyl, each group is optionally substituted by fluorine, methylene di Oxyphenyl or phenyl optionally substituted by R 13 ; R10为氢；氟；任选被氟或氧代取代的甲基；或者未被取代或被C1-C6烷氧基、氧代、氟或以下基团取代的C2-C6烷基：苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基或吗啉基，各基团可以未被取代或被R13取代；或者R 10 is hydrogen; fluorine; methyl optionally substituted by fluorine or oxo; or C 2 -C 6 alkane unsubstituted or substituted by C 1 -C 6 alkoxy, oxo, fluorine or the following groups Base: phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl , tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl or morpholinyl, each group may be unsubstituted or substituted by R 13 ; or R10为苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基或吗啉基，各基团可以未被取代或被R13取代；R 10 is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazole Base, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl or morpholinyl, each group can be unsubstituted or substituted by R 13 ; R11为卤基或任选被氧代取代的C1-C6烷基；R 11 is halo or C 1 -C 6 alkyl optionally substituted by oxo; R12为氢；任选被氟或氧代取代的甲基；任选被苯基、氟或氧代取代的C2-C6烷基；C1-C6三烷基甲硅烷基；芳基烷基甲硅烷基；COR14；COOR14或R 12 is hydrogen; methyl optionally substituted by fluorine or oxo; C 2 -C 6 alkyl optionally substituted by phenyl, fluorine or oxo; C 1 -C 6 trialkylsilyl; Alkylsilyl; COR 14 ; COOR 14 or R13为氟、CF3、任选被羟基或氧代取代的C1-C6烷基或任选被氟取代的C1-C6烷氧基；R 13 is fluorine, CF 3 , C 1 -C 6 alkyl optionally substituted by hydroxyl or oxo, or C 1 -C 6 alkoxy optionally substituted by fluorine; R14为C1-C6烷基或任选被C1-C6烷基或氟取代的苯基；R 14 is C 1 -C 6 alkyl or phenyl optionally substituted by C 1 -C 6 alkyl or fluorine; R15为氢、C1-C6烷基或被R13取代的苯基；R 15 is hydrogen, C 1 -C 6 alkyl or phenyl substituted by R 13 ; R16为任选被氟、氧代或以下基团取代的甲基：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R13取代；或R 16 is methyl optionally substituted by fluorine, oxo or the following groups: phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydro Pyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuranyl, benzothienyl, dihydrobenzo Thienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzisodi Oxolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl Alkyl, each group may be unsubstituted or substituted by R 13 ; or C4-C8环烷基或C2-C6烷基，两种基团均可以未被取代或被氟、甲氧基、任选被苯基或C1-C6烷氧基取代的C2-C6烷氧基、氧代取代，或被以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R13取代；或者C 4 -C 8 cycloalkyl or C 2 -C 6 alkyl, both of which may be unsubstituted or substituted by fluorine, methoxy, optionally phenyl or C 1 -C 6 alkoxy C 2 -C 6 alkoxy, oxo, or substituted by the following groups: phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl , oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, four Hydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuranyl, benzothienyl, dihydrobenzene Thienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzinter Dioxolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl or 1,4-benzobis Oxaalkyl, each group can be unsubstituted or substituted by R 13 ; or C2-C6烷基，它也可以被C4-C8环烷基取代或被苯氧基取代，其中苯氧基可以未被取代或被R6或以下基团取代：苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，各基团可以未被取代或被R13取代；或者C 2 -C 6 alkyl, which may also be substituted by C 4 -C 8 cycloalkyl or substituted by phenoxy, where phenoxy may be unsubstituted or substituted by R 6 or the following groups: phenyl, naphthalene Base, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, Triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazine morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, Benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxa Linyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, each group can be unsubstituted or substituted by R 13 ; or R16为苯基、萘基、呋喃基、噻吩基、吡咯基、四氢呋喃基、吡咯烷基、吡咯啉基、四氢噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、哌啶基、四氢吡喃基、四氢噻喃基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、吗啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、二氢吲哚基、吲唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、二氢苯并吡喃基、二氢苯并噻喃基或1，4-苯并二噁烷基，R 16 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxa Azolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl , pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, dihydroindolyl, indazolyl , benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolinyl, isoquinolyl, Quinazolinyl, quinoxalinyl, dihydrobenzopyranyl, thiochromanyl or 1,4-benzodioxanyl, 各基团可以未被取代或被R13或以下基团取代：苯基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡咯烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、嘧啶基、吲哚基或苯氧基，各基团可以未被取代或被R13取代；Each group can be unsubstituted or substituted by R or the following groups: phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole Base, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl , pyrimidyl, indolyl or phenoxy, each group may be unsubstituted or substituted by R 13 ; X为O或S。X is O or S. 19.权利要求18的方法，其中氢化在碱存在下进行。19. The method of claim 18, wherein the hydrogenation is carried out in the presence of a base. 20.权利要求18的方法，其中所述式V化合物为顺式构型。20. The method of claim 18, wherein the compound of formula V is in the cis configuration. 21.权利要求18的方法，其中所述式IV化合物为外消旋混合物。21. The method of claim 18, wherein the compound of formula IV is a racemic mixture. 22.权利要求18的方法，其中所述式IV化合物为富集对映异构体。22. The method of claim 18, wherein the compound of formula IV is the enriched enantiomer. 23.权利要求22的方法，其中所述式V化合物至少约40％非对映异构体过量。23. The method of claim 22, wherein said compound of formula V is in at least about 40% diastereomeric excess. 24.权利要求18的方法，其中所述催化剂为基于过渡金属的均相催化剂。24. The method of claim 18, wherein the catalyst is a transition metal based homogeneous catalyst. 25.权利要求18的方法，其中所述催化剂选自以下化合物：ClRh[P(Ph)3]3、(1，5-环辛二烯)三环己基膦吡啶铱(I)六氟磷酸盐、(1，5-环辛二烯)双(甲基二苯基膦)铱(I)六氟磷酸盐。25. The method of claim 18, wherein the catalyst is selected from the group consisting of the following compounds: ClRh[P(Ph) 3 ] 3 , (1,5-cyclooctadiene)tricyclohexylphosphinepyridinium(I) hexafluorophosphate , (1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate. 26.权利要求19的方法，其中所述碱选自以下化合物：单(C1-C6烷基)胺、二(C1-C6烷基)胺、三(C1-C6烷基)胺、叔胺、无机碱以及旋光性碱。26. The method of claim 19, wherein the base is selected from the group consisting of mono(C 1 -C 6 alkyl)amines, di(C 1 -C 6 alkyl)amines, tri(C 1 -C 6 alkyl) ) amines, tertiary amines, inorganic bases and optically active bases. 27.权利要求18的方法，其中所述氢源为氢气。27. The method of claim 18, wherein the source of hydrogen is hydrogen gas. 28.权利要求27的方法，其中所述氢化在约大气压至约1,000psi的氢气压力下进行。28. The method of claim 27, wherein the hydrogenation is performed at a hydrogen pressure of from about atmospheric pressure to about 1,000 psi. 29.权利要求28的方法，其中所述氢化在约20psi至约100psi氢气压力下进行。29. The method of claim 28, wherein the hydrogenation is performed at a hydrogen pressure of from about 20 psi to about 100 psi. 30.一种制备式V化合物的方法，该方法包括以下步骤：30. A method for preparing a compound of formula V, the method comprising the steps of: 用拆分剂处理生成式IV化合物的非对映异构体盐；Treat the diastereoisomeric salts of the compound of formula IV with a resolving agent; 用结晶溶剂结晶分离所述非对映异构体盐；separation of said diastereoisomeric salts by crystallization from a crystallization solvent; 在催化剂和溶剂存在下通过氢化还原分离的非对映异构体盐；其中式V和式IV化合物同权利要求18的定义。Diastereoisomeric salts separated by hydrogenation reduction in the presence of a catalyst and a solvent; wherein the compounds of formula V and formula IV are as defined in claim 18. 31.权利要求30的方法，该方法进一步包括以下步骤：通过无机酸水溶液处理将对映体从分离的非对映异构体盐释放出来。31. The method of claim 30, further comprising the step of liberating the enantiomers from the separated diastereomeric salts by treatment with an aqueous mineral acid solution. 32.权利要求30的方法，其中所述还原步骤在碱存在下进行。32. The method of claim 30, wherein said reducing step is performed in the presence of a base. 33.权利要求30或31的方法，其中所述拆分剂为选自以下的旋光性碱：奎宁、辛可宁、(+)-α-甲基苄胺和(-)-α-甲基苄胺。33. The method of claim 30 or 31, wherein the resolving agent is an optically active base selected from the group consisting of quinine, cinchonine, (+)-α-methylbenzylamine and (-)-α-methylbenzylamine amine. 34.权利要求30或31的方法，其中所述结晶溶剂选自以下化合物：乙腈、丙酮、叔丁醇、2-丙醇、乙醇、甲醇以及它们的混合物。34. The method of claim 30 or 31, wherein the crystallization solvent is selected from the group consisting of acetonitrile, acetone, tert-butanol, 2-propanol, ethanol, methanol, and mixtures thereof. 35.一种制备式V化合物的方法，该方法包括以下步骤：35. A method for preparing a compound of formula V, the method comprising the steps of: 通过在氢化催化剂和溶剂存在下的氢化将式IV化合物还原为式V化合物；reducing the compound of formula IV to the compound of formula V by hydrogenation in the presence of a hydrogenation catalyst and a solvent; 用拆分剂处理生成式V化合物的非对映异构体盐；Treat the diastereoisomeric salts of the compound of formula V with a resolving agent; 在结晶溶剂中结晶从而分离非对映异构体盐；separation of diastereoisomeric salts by crystallization in a crystallization solvent; 通过无机酸水溶液处理将各个对映体从分离的盐中释放出来；Liberation of the individual enantiomers from the separated salts by treatment with aqueous mineral acid; 其中式V和式IV化合物同权利要求18的定义。Wherein the compound of formula V and formula IV is as defined in claim 18. 36.权利要求35的方法，其中所述还原步骤在碱存在下进行。36. The method of claim 35, wherein said reducing step is performed in the presence of a base. 37.权利要求35或36的方法，其中所述氢化催化剂选自以下化合物：ClRh[P(Ph)3]3、(1，5-环辛二烯)三环己基膦吡啶铱(I)六氟磷酸盐和(1，5-环辛二烯)双(甲基二苯基膦)铱(I)六氟磷酸盐。37. The method of claim 35 or 36, wherein the hydrogenation catalyst is selected from the following compounds: ClRh[P(Ph) 3 ] 3 , (1,5-cyclooctadiene)tricyclohexylphosphinepyridineiridium(I)hexa Fluorophosphate and (1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate. 38.权利要求35或36的方法，其中所述拆分剂选自以下化合物：奎宁、辛可宁、(+)-α-甲基苄胺和(-)-α-甲基苄胺。38. The method of claim 35 or 36, wherein the resolving agent is selected from the group consisting of quinine, cinchonine, (+)-α-methylbenzylamine and (-)-α-methylbenzylamine. 39.权利要求35或36的方法，其中所述结晶溶剂选自以下化合物：乙腈、丙酮、叔丁醇、2-丙醇、乙醇、甲醇以及它们的混合物。39. The method of claim 35 or 36, wherein the crystallization solvent is selected from the group consisting of acetonitrile, acetone, t-butanol, 2-propanol, ethanol, methanol, and mixtures thereof. 40.一种药用组合物，该组合物包含有效量权利要求1的化合物或其药学上可接受的盐以及药学上可接受的载体。40. A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 41.一种药用组合物，该组合物包含有效量权利要求7或8的化合物或其药学上可接受的盐以及药学上可接受的载体。41. A pharmaceutical composition comprising an effective amount of the compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 42.一种药用组合物，该组合物包含有效量权利要求9的化合物或其药学上可接受的盐以及药学上可接受的载体。42. A pharmaceutical composition comprising an effective amount of the compound of claim 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 43.一种药用组合物，该组合物包含有效量权利要求10的化合物或其药学上可接受的盐以及药学上可接受的载体。43. A pharmaceutical composition comprising an effective amount of the compound of claim 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 44.一种药用组合物，该组合物包含有效量权利要求11的化合物或其药学上可接受的盐以及药学上可接受的载体。44. A pharmaceutical composition comprising an effective amount of the compound of claim 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 45.一种药用组合物，该组合物包含有效量权利要求12的化合物或其药学上可接受的盐以及药学上可接受的载体。45. A pharmaceutical composition comprising an effective amount of the compound of claim 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 46.一种药用组合物，该组合物包含有效量权利要求13的化合物或其药学上可接受的盐以及药学上可接受的载体。46. A pharmaceutical composition comprising an effective amount of the compound of claim 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 47.一种药用组合物，该组合物包含有效量权利要求14的化合物或其药学上可接受的盐以及药学上可接受的载体。47. A pharmaceutical composition comprising an effective amount of the compound of claim 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 48.一种药用组合物，该组合物包含有效量权利要求15的化合物或其药学上可接受的盐以及药学上可接受的载体。48. A pharmaceutical composition comprising an effective amount of the compound of claim 15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 49.一种药用组合物，该组合物包含有效量权利要求16的化合物或其药学上可接受的盐以及药学上可接受的载体。49. A pharmaceutical composition comprising an effective amount of the compound of claim 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 50.一种组合物，该组合物包含有效量权利要求1的化合物或者其盐以及惰性载体。50. A composition comprising an effective amount of the compound of claim 1 or a salt thereof and an inert carrier. 51.一种组合物，该组合物包含有效量权利要求9的化合物或者其盐以及惰性载体。51. A composition comprising an effective amount of the compound of claim 9 or a salt thereof and an inert carrier. 52.一种组合物，该组合物包含有效量权利要求11的化合物或者其盐以及惰性载体。52. A composition comprising an effective amount of the compound of claim 11 or a salt thereof and an inert carrier. 53.一种组合物，该组合物包含有效量权利要求13的化合物或者其盐以及惰性载体。53. A composition comprising an effective amount of the compound of claim 13 or a salt thereof and an inert carrier. 54.一种组合物，该组合物包含有效量权利要求15的化合物或者其盐以及惰性载体。54. A composition comprising an effective amount of the compound of claim 15 or a salt thereof and an inert carrier. 55.权利要求1的化合物在制备用于治疗糖尿病的药物中的应用。55. Use of the compound of claim 1 for the preparation of a medicament for the treatment of diabetes. 56.权利要求1的化合物在制备用于治疗X综合征的药物中的应用。56. Use of the compound of claim 1 for the preparation of a medicament for the treatment of Syndrome X. 57.权利要求1的化合物在制备用于治疗糖尿病相关性疾病的药物中的应用。57. Use of the compound of claim 1 in the preparation of a medicament for treating diabetes-related diseases. 58.权利要求57的应用，其中所述糖尿病相关性疾病选自以下疾病：高血糖、高胰岛素血症、葡萄糖耐量降低、空腹血糖升高、异常脂血症、高甘油三酯血症和胰岛素抵抗。58. The use of claim 57, wherein the diabetes-related disease is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, elevated fasting blood glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance. 59.权利要求1的化合物在制备用于治疗心血管疾病的药物中的应用。59. Use of the compound of claim 1 for the preparation of a medicament for the treatment of cardiovascular diseases. 60.权利要求59的应用，其中所述心血管疾病选自以下疾病：动脉粥样硬化病、异常脂血症、高胆固醇血症、HDL降低、高血压、冠心病和冠状动脉病。60. The use of claim 59, wherein the cardiovascular disease is selected from the group consisting of atherosclerotic disease, dyslipidemia, hypercholesterolemia, HDL reduction, hypertension, coronary heart disease and coronary artery disease. 61.权利要求1的化合物在制备用于治疗脑血管疾病的药物中的应用。61. Use of the compound of claim 1 in the preparation of a medicament for the treatment of cerebrovascular diseases. 62.权利要求1的化合物在制备用于治疗外周血管病的药物中的应用。62. Use of the compound of claim 1 for the preparation of a medicament for the treatment of peripheral vascular diseases. 63.权利要求1的化合物在制备用于治疗多囊卵巢病的药物中的应用。63. Use of the compound of claim 1 for the preparation of a medicament for the treatment of polycystic ovary disease. 64.权利要求9的化合物在制备用于治疗糖尿病的药物中的应用。64. Use of the compound of claim 9 for the preparation of a medicament for the treatment of diabetes. 65.权利要求9或11的化合物在制备用于治疗X综合征的药物中的应用。65. Use of a compound according to claim 9 or 11 for the preparation of a medicament for the treatment of syndrome X. 66.权利要求9或11的化合物在制备用于治疗糖尿病相关性疾病的药物中的应用。66. Use of a compound according to claim 9 or 11 for the preparation of a medicament for treating diabetes-related diseases. 67.权利要求66的应用，其中所述糖尿病相关性疾病选自以下疾病：高血糖、高胰岛素血症、葡萄糖耐量降低、空腹血糖升高、异常脂血症、高甘油三酯血症和胰岛素抵抗。67. The use of claim 66, wherein the diabetes-related disease is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, elevated fasting blood glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance. 68.权利要求9或11的化合物在制备用于治疗心血管疾病的药物中的应用。68. Use of a compound according to claim 9 or 11 for the preparation of a medicament for the treatment of cardiovascular diseases. 69.权利要求68的应用，其中所述心血管疾病选自以下疾病：动脉粥样硬化病、异常脂血症、高胆固醇血症、HDL降低、高血压、冠心病和冠状动脉病。69. The use of claim 68, wherein the cardiovascular disease is selected from the group consisting of atherosclerotic disease, dyslipidemia, hypercholesterolemia, HDL reduction, hypertension, coronary heart disease and coronary artery disease. 70.权利要求9或11的化合物在制备用于治疗脑血管疾病的药物中的应用。70. Use of a compound according to claim 9 or 11 for the preparation of a medicament for the treatment of cerebrovascular diseases. 71.权利要求9或11的化合物在制备用于治疗外周血管病的药物中的应用。71. Use of a compound according to claim 9 or 11 for the preparation of a medicament for the treatment of peripheral vascular diseases. 72.权利要求9或11的化合物在制备用于治疗多囊卵巢病的药物中的应用。72. Use of a compound according to claim 9 or 11 for the preparation of a medicament for the treatment of polycystic ovary disease. 73.权利要求13的化合物在制备用于治疗糖尿病的药物中的应用。73. Use of the compound of claim 13 for the preparation of a medicament for the treatment of diabetes. 74.权利要求13的化合物在制备用于治疗X综合征的药物中的应用。74. Use of the compound of claim 13 for the preparation of a medicament for the treatment of Syndrome X. 75.权利要求13的化合物在制备用于治疗糖尿病相关性疾病的药物中的应用。75. Use of the compound of claim 13 in the preparation of a medicament for treating diabetes-related diseases. 76.权利要求75的应用，其中所述糖尿病相关性疾病选自以下疾病：高血糖、高胰岛素血症、葡萄糖耐量降低、空腹血糖升高、异常脂血症、高甘油三酯血症和胰岛素抵抗。76. The use of claim 75, wherein the diabetes-related disease is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, elevated fasting blood glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance. 77.权利要求13的化合物在制备用于治疗心血管疾病的药物中的应用。77. Use of the compound of claim 13 for the preparation of a medicament for the treatment of cardiovascular diseases. 78.权利要求77的应用，其中所述心血管疾病选自以下疾病：动脉粥样硬化病、异常脂血症、高胆固醇血症、HDL降低、高血压、冠心病和冠状动脉病。78. The use of claim 77, wherein the cardiovascular disease is selected from the group consisting of atherosclerotic disease, dyslipidemia, hypercholesterolemia, HDL reduction, hypertension, coronary heart disease and coronary artery disease. 79.权利要求13的化合物在制备用于治疗脑血管疾病的药物中的应用。79. Use of the compound of claim 13 in the preparation of a medicament for the treatment of cerebrovascular diseases. 80.权利要求13的化合物在制备用于治疗外周血管病的药物中的应用。80. Use of the compound of claim 13 for the preparation of a medicament for the treatment of peripheral vascular disease. 81.权利要求13的化合物在制备用于治疗多囊卵巢病的药物中的应用。81. Use of the compound of claim 13 for the preparation of a medicament for the treatment of polycystic ovary disease. 82.权利要求15的化合物在制备用于治疗糖尿病的药物中的应用。82. Use of the compound of claim 15 for the preparation of a medicament for the treatment of diabetes. 83.权利要求15的化合物在制备用于治疗X综合征的药物中的应用。83. Use of the compound of claim 15 for the preparation of a medicament for the treatment of Syndrome X. 84.权利要求15的化合物在制备用于治疗糖尿病相关性疾病的药物中的应用。84. Use of the compound of claim 15 in the preparation of a medicament for treating diabetes-related diseases. 85.权利要求84的应用，其中所述糖尿病相关性疾病选自以下疾病：高血糖、高胰岛素血症、葡萄糖耐量降低、空腹血糖升高、异常脂血症、高甘油三酯血症和胰岛素抵抗。85. The use of claim 84, wherein said diabetes-related disease is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, elevated fasting blood glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance. 86.权利要求15的化合物在制备用于治疗心血管疾病的药物中的应用。86. Use of the compound of claim 15 for the preparation of a medicament for the treatment of cardiovascular diseases. 87.权利要求86的应用，其中所述心血管疾病选自以下疾病：动脉粥样硬化病、异常脂血症、高胆固醇血症、HDL降低、高血压、冠心病和冠状动脉病。87. The use of claim 86, wherein the cardiovascular disease is selected from the group consisting of atherosclerotic disease, dyslipidemia, hypercholesterolemia, HDL reduction, hypertension, coronary heart disease and coronary artery disease. 88.权利要求15的化合物在制备用于治疗脑血管疾病的药物中应用。88. The use of the compound of claim 15 in the preparation of a medicament for the treatment of cerebrovascular diseases. 89.权利要求15的化合物在制备用于治疗外周血管病的药物中的应用。89. Use of the compound of claim 15 for the preparation of a medicament for the treatment of peripheral vascular diseases. 90.权利要求15的化合物在制备用于治疗多囊卵巢病的药物中的应用。90. Use of the compound of claim 15 for the preparation of a medicament for the treatment of polycystic ovary disease.
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